Speaker 1: As long as I could remember, in my early childhood,
Speaker 1: I always knew that my dad had hemophilia. I can
Speaker 1: specifically remember we had a whole shelf in our refrigerator
Speaker 1: full of these little white boxes of factor nine, which
Speaker 1: as a kid, I didn't really know what they were,
Speaker 1: but I knew, like, pretty frequently my dad would have
Speaker 1: to take one of those boxes into his room and
Speaker 1: he'd close the door and we'd have to leave him
Speaker 1: alone for an hour, and as I learned as I
Speaker 1: got a little older, he would be transfusing himself with
Speaker 1: factor nine. He was a wonderful dad, but you know,
Speaker 1: because of a long history of bleeding into his joints,
Speaker 1: he couldn't interact with us the same way maybe other
Speaker 1: dads would. He had a lot of joint pain and
Speaker 1: it was visible in his hands and his feet, and
Speaker 1: he would try his best, but I think I drove
Speaker 1: him crazy wanting to be carried constantly, which he could
Speaker 1: not do, and we just always wanted to, you know,
Speaker 1: play like little kids do, and he'd have to try
Speaker 1: his best and then step back from that. I'm sure
Speaker 1: we probably contributed to him needing to transfuse more than
Speaker 1: otherwise he would have but that's okay. He never minded,
Speaker 1: He never complained at all. So when I reached around puberty,
Speaker 1: maybe I was told earlier, but I definitely distinctly remember
Speaker 1: being told, you know, hemophilia is genetic, and that they
Speaker 1: found out when I was born that I was a carrier,
Speaker 1: but they would need to find out if I was
Speaker 1: a symptomatic carrier. So in my probaly between ten and twelve,
Speaker 1: went to the hospital, got some tests done and found out,
Speaker 1: sure enough, I am a carrier, and not only that,
Speaker 1: but a symptomatic carrier. Nowadays, they actually just consider women
Speaker 1: who carry that gena dar symptomatic to just have chemophilia.
Speaker 1: They don't call symptomatic carriers anymore. So, like my dad
Speaker 1: and actually both of his brothers, I have hemophilia B,
Speaker 1: a factor nine deficiency. Unlike them, mine is mild and
Speaker 1: doesn't affect my life day to day, since two out
Speaker 1: of the three of them are no longer alive to
Speaker 1: speak to their own stories and tell you a little
Speaker 1: about them. So, my dad and his older brother both
Speaker 1: had very severe chemophilia B. They produced zero factor nine
Speaker 1: on their own, and they were born in the nineteen fifties,
Speaker 1: which was before pretty much any good treatment existed. All
Speaker 1: three brothers, actually, my grandmother used to tell me, they
Speaker 1: refused to cooperate with all the restrictions on their behavior,
Speaker 1: and at the time, the lifespan for them was expected
Speaker 1: to only be into their twenties, so my grandmother tried
Speaker 1: as hard as she could to keep three young boys
Speaker 1: well contained, and they didn't cooperate at all. My dad
Speaker 1: even at one point took me down the road from
Speaker 1: his old house to show me the field where they
Speaker 1: would all go play football and subsequently all need to
Speaker 1: be driven to the hospital to get blood transfusions. So
Speaker 1: my grandmother said their childhood was full of at least
Speaker 1: one trip to the hospital every week, and it was
Speaker 1: so frequent that their pediatrician would actually pick them up
Speaker 1: at her house and bring them there himself. I can't
Speaker 1: imagine having a childhood like that, and I also suspect
Speaker 1: it probably contributed to a lot of the symptoms my
Speaker 1: dad had just from just constant bleeding. But I also
Speaker 1: can't imagine living a life as restricted as kids with
Speaker 1: humohilia really needed to Back then, when I was actually
Speaker 1: soon after I found out that I was also a
Speaker 1: carrier and symptomatic with humophilia. My uncle became symptomatic with
Speaker 1: his HIV, had SYRUH converted to AIDS, and I never
Speaker 1: knew growing up that he had HIV, and I never
Speaker 1: knew that my dad had hepatitis C. But when he
Speaker 1: got really sick, my dad found it important to sit
Speaker 1: us down and tell both me and my sister that
Speaker 1: that they both developed HIV, and then my dad HEPSI
Speaker 1: and my uncle as well HEPSI as a result of
Speaker 1: blood transfusions and blood products because back when they were
Speaker 1: young and getting them, they didn't know that they contained
Speaker 1: all these viruses. And they told me then that about
Speaker 1: half of all people with hemophilia back then would go
Speaker 1: on to get these diseases, and never really gave me
Speaker 1: a number on how many of them died, but I
Speaker 1: understood them that it was pretty grave. So when I
Speaker 1: was fourteen, my uncle passed away from implications from HIV
Speaker 1: and AIDS that again he contracted as a result of
Speaker 1: treatment for his hemophilia. When I was in my early twenties,
Speaker 1: my dad also passed away from complications of hepatitis C,
Speaker 1: again from requiring blood products for hemophilia. I remember for
Speaker 1: my dad it was really profound he actually, up until
Speaker 1: the point that he got really critical with his hepsia,
Speaker 1: had said that it was almost like a silver lining
Speaker 1: of hemophilia to get hepatitis c because a liver transplant
Speaker 1: actually would have functionally cured his hemophilia, and he felt
Speaker 1: that life post transplant would have been a better quality
Speaker 1: than that of living with hemophilia, even with home transfusions
Speaker 1: and all the other treatment options, which is really devastating
Speaker 1: to think about, especially knowing how positively he viewed life
Speaker 1: and how little he complained. So for me personally, like
Speaker 1: I said, day to day, my quality of life isn't impacted,
Speaker 1: although I do have other medical issues and hemophilia always
Speaker 1: complicates those. So when I go to a doctor and
Speaker 1: we're talking about treatment options for other things, my bleeding
Speaker 1: and clouding status is always at the forefront of my
Speaker 1: doctor's minds. Whether I need to be hospitalized inpatient for
Speaker 1: something that other people would go home from the same day,
Speaker 1: whether I need to be infused with factor before during
Speaker 1: after the next day, whether I need to take something
Speaker 1: like amacar for a mild procedure, and even down to
Speaker 1: the reason I had had to go back when I
Speaker 1: hit puberty for periods which are heavy and really unpleasant,
Speaker 1: which everybody deals with, I'm sure, but for someone with
Speaker 1: heem affiliates particular gularly burdensome. And I always worry if
Speaker 1: I get into a car accident or some sort of
Speaker 1: other trauma, if I don't go to a hospital that
Speaker 1: has my records or my husband's not with me to
Speaker 1: tell somebody when I'm bleeding. Will they give me normal
Speaker 1: blood or red blood cells, which will only thin out
Speaker 1: my factor levels even more, dilute them even more, or
Speaker 1: will I be okay? But mostly I'm grateful that I
Speaker 1: was born when I was in the eighties. I'm grateful
Speaker 1: that one of my uncles is still alive, that he
Speaker 1: was born later than the other two and has suffered
Speaker 1: less because things like cryo precipitate were already known about
Speaker 1: in his early childhood. And other than that, I think
Speaker 1: that hemophilia is It's not something we hear about regularly,
Speaker 1: but it's it's a fascinating look at a disease that
Speaker 1: can just ravage an entire family line, one that can
Speaker 1: have devastating impacts if it's not diagnosed early. Living with
Speaker 1: humophilia now is so much easier than it used to be.
Speaker 1: But I think that even though the treatment options have
Speaker 1: improved dramatically, we can look back at the very recent
Speaker 1: history of this disease and see that it's really important
Speaker 1: to evaluate, you know, looking for treatment options, but also
Speaker 1: evaluating the safety of them, because the impacts that they
Speaker 1: can have on the people that we're treating can be
Speaker 1: really devastating.
Speaker 2: Thank you so much for taking the time to chat
Speaker 2: with us and for sharing your story.
Speaker 3: We appreciate it.
Speaker 2: Hi, I'm erin Welsh.
Speaker 3: And I'm erin Oman Updyke.
Speaker 2: And this is this podcast will Kill You.
Speaker 3: And welcome. I lost track of our episode numbers again.
Speaker 3: It's over seventy something.
Speaker 2: Yeah, I think this is seventy nine. How I know,
Speaker 2: let us go, I know, I know we're getting up there.
Speaker 3: We really are.
Speaker 1: Well.
Speaker 3: Welcome everyone. I'm pretty excited about this episode me too.
Speaker 2: It's kind of an unusual one, different in that for
Speaker 2: a number of reasons. Number one, it's not an infectious
Speaker 2: disease m H. And number two maybe this doesn't make
Speaker 2: it different, but like the research turned out to be
Speaker 2: a lot different than I expected.
Speaker 3: Yeah for me as well. And I'm really excited about
Speaker 3: the biology section because it's totally different than what I
Speaker 3: normally do in this series.
Speaker 2: Yeah, I feel like it's going to be a really
Speaker 2: interesting one to kind of dive into parts that we
Speaker 2: don't usually talk about or have only touched on briefly. Yeah,
Speaker 2: and also because the history for this is so massive,
Speaker 2: I like barely stumbled onto any biology, and so I'm
Speaker 2: really excited to learn exactly how these different things happen.
Speaker 2: But arin, what are we talking about today? Today?
Speaker 3: We're talking about hemophilia.
Speaker 2: Yes we are, which is also kind of like with
Speaker 2: our last episode, Bartonella, an umbrella term for a lot
Speaker 2: of different types of things.
Speaker 3: It is, it is. But luckily the biology is not
Speaker 3: nearly as confusing as Bartonella. It's like all very straightforward.
Speaker 2: It would be surprising if it were as confusing as Martinella.
Speaker 2: I don't know if there's anything quite as confusing as that.
Speaker 3: Let's hope. Let's hope not.
Speaker 2: Yeah.
Speaker 3: Well, in the interest of how long this episode's going
Speaker 3: to be, I think it's about time for a quarantini
Speaker 3: it is.
Speaker 2: What are we drinking this week?
Speaker 3: We're drinking the transfusion. Get it, like a blood blood
Speaker 3: transit you get it? You can up with it.
Speaker 2: I get it. I get it.
Speaker 3: Aaron, what's in the transfusion?
Speaker 2: It is whiskey, simple syrup, blood, orange juice, lemon juice,
Speaker 2: lime juice, and grenadine.
Speaker 3: Niceon red, very red, very red.
Speaker 2: And we will post the full recipe for this quarantini
Speaker 2: as well as the non alcoholic place sy burrita on
Speaker 2: our website This podcast will kill You dot Com, as
Speaker 2: well as on all of our social media channels.
Speaker 3: Speaking of our website, this podcast would kill you dot Com.
Speaker 3: If you haven't checked it out, you should definitely do so.
Speaker 3: We have so many things there, from merch to transcripts,
Speaker 3: to links to our music, to our Patreon to every
Speaker 3: source we've ever used in an episode. We've got bookshop,
Speaker 3: We've got a good Reads list. Oh my gosh, there's
Speaker 3: so much there. Check it out.
Speaker 2: Yeah, there's a lot, there's a long list.
Speaker 3: I ran out of breath.
Speaker 2: Well, I think that's good timing because I think we're
Speaker 2: ready to just dive into the episode.
Speaker 3: I think, so this is going to be a good one.
Speaker 3: Let's take a quick break and then get straight to it.
Speaker 3: So Hemophilia, I'm not gonna step on your toes erin,
Speaker 3: but obviously Heme is blood and phil is love, so
Speaker 3: hemophilia is love to bleed.
Speaker 2: I okay, I don't really love that name for it.
Speaker 2: I don't know why.
Speaker 3: It's not great, but it's very what is it Greek,
Speaker 3: Latin Latin? Sure? Yeah. Anyways, So hemophilia is a disorder
Speaker 3: of blood clotting, and once you understand what is missing,
Speaker 3: what the essential underlying problem is, all of the symptoms
Speaker 3: that make up the disorder become incredibly clear because they're
Speaker 3: essentially just problems that will then lead to bleeding, which spoiler,
Speaker 3: those are the main symptoms. So this episode's fun because
Speaker 3: we're gonna go over in very general terms some really
Speaker 3: basic human biology, and that is the clotting cascade.
Speaker 2: Oh okay, I was hoping I was gonna learn about this.
Speaker 3: That's pretty much gonna be the main that's the whole
Speaker 3: biology section. Great, okay, because once you understand how our
Speaker 3: blood normally clots, then all of the problems that arise
Speaker 3: from hemophilia, they're just like an extension of that. It's
Speaker 3: a direct consequence of interrupting this clotting process.
Speaker 2: Right, Okay.
Speaker 3: I will say upfront, if you are someone who needs
Speaker 3: or wants to memorize all of the details of this process,
Speaker 3: like every number of every factor. I'm not going to
Speaker 3: go into that, but I'll link to a con Academy
Speaker 3: video that's excellent. We're just gonna go over it in
Speaker 3: pretty broad strokes, all right, So everyone knows that our
Speaker 3: blood is very important in our bodies. It's how we
Speaker 3: carry nutrients and oxygen to all of our tissues, and
Speaker 3: it's how our cells offload carbon dioxide and waste products
Speaker 3: to be carried to our lungs, our liver, et cetera.
Speaker 3: And in our human bodies, blood is inside of blood vessels,
Speaker 3: and that's where it's supposed to remain. If the walls
Speaker 3: of our blood vessels get broken, we bleed. We all
Speaker 3: know this, right. If you get a cut on your skin,
Speaker 3: you break the walls of tiny little blood vessels and
Speaker 3: you bleed. And because bleeding outside of our vessels is bad,
Speaker 3: our body has mechanisms to stop this from bleeding. Everything
Speaker 3: from tiny scratches up to larger breaks in the vessels.
Speaker 3: So very broadly, when a blood vessel wall gets disrupted,
Speaker 3: there's kind of a series of three steps that happen
Speaker 3: to fix it. First, you plug the hole like stick
Speaker 3: your finger in it kind of plug, just so that
Speaker 3: you don't lose any more blood. Second, you a fix
Speaker 3: that plug into place with something a little bit more
Speaker 3: sturdy so it doesn't come unplugged in like the near term.
Speaker 3: And then finally you have to prepare that whole area,
Speaker 3: if possible, so you don't break it in the same spot.
Speaker 2: Right.
Speaker 3: So, the way I like to think of it is
Speaker 3: if our bodies were like the plumbing under your sink.
Speaker 3: You're like, oh my god, I just sprung a leak.
Speaker 3: I don't want to flood my whole house. So you
Speaker 3: pull your gum out of your mouth and shove it
Speaker 3: over the leak step one. And then you go search
Speaker 3: your whole house to find the duct tape that you
Speaker 3: know you had somewhere, and you secure that gum in
Speaker 3: place with a whole bunch of duct tape just to
Speaker 3: keep it until you can call the plumber, who might
Speaker 3: take their sweet time getting over there. But that duct
Speaker 3: tape is strong, so it'll hold it until it can
Speaker 3: be fixed properly. Easy, easy, Right, That's what we do
Speaker 3: in our human pipes. When a blood vessel wall is disrupted,
Speaker 3: the first thing that happens is our platelets, which I
Speaker 3: feel like we've talked about a bit on this podcast.
Speaker 3: Platelets are just these little cells, kind of little chunks
Speaker 3: of cells that are in our bloodstream and they're super sticky,
Speaker 3: so they float past that hole in the blood vessel
Speaker 3: wall and they stick themselves. They turn on their stickiness
Speaker 3: and they stick themselves to just plug that hole. First thing,
Speaker 3: gum in the hole. That's your platelets. But gum that
Speaker 3: you just threw down in a panic doesn't hold that
Speaker 3: flow forever. And obviously in our bodies, we can't just
Speaker 3: like find duct tape, right because if you had a
Speaker 3: bunch of duct tape just floating around your bodies, you'd
Speaker 3: be clogging up your pipes because duct tape is really sticky.
Speaker 3: So we in our bodies have to actually make the
Speaker 3: duct tape from scratch, and that is where the coagulation
Speaker 3: cascade comes in.
Speaker 2: Ahhh okay, okay, So.
Speaker 3: The duct tape in our bodies is a substance called fibrin.
Speaker 3: Fibrin is a really strong sticky protein that cross links
Speaker 3: kind of just like duct tape honestly, and forms these
Speaker 3: chains to make a really nice solid patch to hold
Speaker 3: that blood vessel wall until we can call the plumber
Speaker 3: and actually repair those endothelial cells themselves. But like I said,
Speaker 3: fibrin doesn't just float around our bloodstream freely. It has
Speaker 3: to be activated before it can do its job. And
Speaker 3: the series of events that have to take place, it's
Speaker 3: kind of maybe I'm getting too excited about it, but
Speaker 3: it is the coagulation cascade. And if any listeners have
Speaker 3: seen this drawn out on paper aerin, you probably have
Speaker 3: way long time ago.
Speaker 2: Right, probably probably.
Speaker 3: It's like a Y shaped little graphic. It has two
Speaker 3: arms and then they come together at the bottom because
Speaker 3: the bottom is fibrin. So it's a process that begins
Speaker 3: as soon as a vessel wall is disrupted. It involves
Speaker 3: twelve different proteins, although they're numbered like one through thirteen,
Speaker 3: and there's no number six.
Speaker 2: Okay, okay, listen.
Speaker 3: They thought that six was turned out to be a
Speaker 3: part of another one they had named one six and
Speaker 3: then it was like, oh, just kidding, that's something else
Speaker 3: like Pluto of exactly poor Pluto. So all these different
Speaker 3: proteins are called factors factor one through thirteen minus six,
Speaker 3: and they all essentially help catalyze the activation of each
Speaker 3: other down a chain. Really, it's down two different arms
Speaker 3: of a chain that lead to the same place, and
Speaker 3: that same place is an exponential increase in activated fibrin
Speaker 3: aka duct tape. I'm not going to go over the
Speaker 3: specific series of events because it's not really that important
Speaker 3: for this, but you can imagine that if number one
Speaker 3: is fibrin, which it is, and number twelve is like
Speaker 3: the top of the chain, you kind of are moving
Speaker 3: down to try and make fibrin. So anything that's missing
Speaker 3: or doesn't work correctly between numbers two and eleven means
Speaker 3: that you're going to interrupt that whole process and not
Speaker 3: be able to make fibrine.
Speaker 2: But the interruptions are not equal, right in that, like,
Speaker 2: if you stop earlier on, you're gonna have an even
Speaker 2: less finished product than if you stop at like factor ten.
Speaker 3: Absolutely, yes, okay, And on top of that, there's two
Speaker 3: arms of this chain, so even if you're missing, you know,
Speaker 3: a bunch of one of those arms, you'll still have
Speaker 3: a little bit with that other arm, gotcha. So yes, However,
Speaker 3: a disruption anywhere in that chain is going to affect clotting,
Speaker 3: but all to a different degree.
Speaker 2: Mm hmm.
Speaker 3: So it's a fairly complex series of events, but It
Speaker 3: makes sense that it's complex because this is a process
Speaker 3: that you do not want happening uncontrolled. Right, It's very
Speaker 3: important to be able to form these super stable clots,
Speaker 3: but you don't want this process running a muck and
Speaker 3: making clots when it shouldn't because when that happens, and
Speaker 3: it does, that's called a thrombophilia, meaning you love making clots.
Speaker 2: Right, and so it's deadlier to have more of the
Speaker 2: stuff running around, probably, which is why there are so
Speaker 2: many switches that need to be activated.
Speaker 3: Right. I don't have numbers on whether they're equally deadly
Speaker 3: or not, but they're both bad.
Speaker 2: They're both bad.
Speaker 3: Yeah, yeah, So yeah, it's this series of events. That's
Speaker 3: why we call it a cascade. Each step from twelve
Speaker 3: to ten to nine and eight to five. It actually
Speaker 3: goes from twelve to eleven to nine. Long story. Each
Speaker 3: step has to take place in order to build that
Speaker 3: final product, like an assembly line. So hemophilia is a disorder.
Speaker 3: It's several disorders that interrupt this process because of either
Speaker 3: inadequate production or production but incorrect or inadequate activity of
Speaker 3: certain factors in this clotting cascade. Okay, so, like you mentioned,
Speaker 3: Aaron early on. There's a number of different types of hemophilia.
Speaker 3: They all have slightly different clinical pictures, but overall, if
Speaker 3: you think of them as not being able to clot
Speaker 3: blood efficiently, then they're all pretty similar. So hemophilia A,
Speaker 3: which is the most common, is when you have a
Speaker 3: problem in the production of factor eight. That's one very
Speaker 3: important factor in the clotting cascade. Hemophilia B is when
Speaker 3: there's a problem with the production of factor nine. And
Speaker 3: those two are the kind of main diseases that we
Speaker 3: call hemophilia, And they actually look very similar because factor
Speaker 3: nine in factor eight work together in the clotting cascade.
Speaker 3: So those two diseases are like very very similar. Clinically
Speaker 3: they look about the same. You have to do like
Speaker 3: factor analysis how much factor eight versus how much factor
Speaker 3: nine do you have in your blood to know which
Speaker 3: one you have?
Speaker 2: Okay, gotcha.
Speaker 3: But then there are other hemophilias. Hemophilias is really the
Speaker 3: only other one that's often called like hemophilia proper, and
Speaker 3: that's a problem in the production of factor eleven. But
Speaker 3: problems at any point along this cascade lead to varying
Speaker 3: degrees of what we call coagulopathies just problems with coagulation.
Speaker 3: Does that all make sense?
Speaker 2: Yeah, I'm with you.
Speaker 3: Pretty big picture, but pretty like logical. It's an assembly line.
Speaker 3: If you take out pieces, you don't get the final
Speaker 3: product mm hm to one degree or another. So how
Speaker 3: do you actually get this disease? Great question, Thanks for asking.
Speaker 3: We'll focus for this part on hemophilia A and talk
Speaker 3: also a little bit about hemophilia B because these are,
Speaker 3: of course the two classic forms of hemophilia. These are
Speaker 3: the two that people think of the most, and when
Speaker 3: you google hemophilia, that's what you get. So these are
Speaker 3: both genetic disorders, and both hemphilia A and hemophilia B
Speaker 3: are X linked recessive disorders. I don't think we've covered
Speaker 3: any of these, have.
Speaker 2: We, Eric, I don't think so.
Speaker 3: I don't think so. So this is kind of fun.
Speaker 3: X linked recessive just means that the genes that encode
Speaker 3: for these two proteins, factor eight and factor nine are
Speaker 3: found on the X chromosome. About fifty percent of the
Speaker 3: population only has one copy of that X chromosome, so
Speaker 3: they are more susceptible to this disease, more likely to
Speaker 3: get it because they just have the one copy of
Speaker 3: the X and if they have a mutated copy of
Speaker 3: factor eight or nine gene, then they're gonna have symptoms
Speaker 3: of hemophilia to one degree or another. If you have
Speaker 3: two copies of the X chromosome, then you most likely
Speaker 3: won't have any symptoms of disease, but you will be
Speaker 3: what's called a carrier because you have that mutated gene
Speaker 3: and can then pass it on to offspring. And this
Speaker 3: makes sense because I said that this was all a cascade, right,
Speaker 3: You only need a very little bit of factor eight
Speaker 3: or factor nine to be able to effectively activate this cascade.
Speaker 3: So you have to have a reduction of like eighty
Speaker 3: to ninety five percent of typical plasma levels of factor
Speaker 3: eight in your blood to actually have symptoms of hemophilia.
Speaker 3: So if you have even just one normal gene that
Speaker 3: makes a little bit of factor eight, then you're not
Speaker 3: gonna have symptoms of hemophilia.
Speaker 1: Right.
Speaker 3: So it's a lot like cystic fibrosis when we talked
Speaker 3: about that, Right, there's a lot of different ways that
Speaker 3: this protein can be mutated. So there's a whole bunch
Speaker 3: of different specific mutations that you can have, but they
Speaker 3: all result in this protein either being not there at
Speaker 3: all or not functional.
Speaker 2: Is it less of a spectrum than in cystic fibrosis,
Speaker 2: Like you said that it needs to be a ninety
Speaker 2: or eighty to ninety percent reduction in the presence of
Speaker 2: whatever factor to activate this cascade, But how often do
Speaker 2: numbers like forty or is this just like the clinical
Speaker 2: picture is either eighty to ninety percent is when it
Speaker 2: shows up clinically and everything else is subclinical.
Speaker 3: Yeah, yeah, great question. So it's a really wide spectrum
Speaker 3: of disease even clinically, right, And that's because you don't
Speaker 3: even start to show symptoms until you get to like
Speaker 3: an eighty to ninety percent reduction for the most part.
Speaker 3: But if someone has like fifty percent less factor ate
Speaker 3: and then they have a massive surgery of some kind,
Speaker 3: they're probably going to bleed more and longer than someone
Speaker 3: who has a normal level of factor eight. So are
Speaker 3: they ever going to have other symptoms in a life
Speaker 3: where they didn't have any surgeries? Maybe not. So there's
Speaker 3: there is a huge spectrum and then even between eighty percent,
Speaker 3: Like if you have an eighty percent reduction, so you
Speaker 3: have twenty percent of factor eight versus someone who has
Speaker 3: zero factor eight. There's a huge spectrum of disease severity
Speaker 3: within that as well.
Speaker 2: Okay, and so talking about those mutations then, and what
Speaker 2: leads to eighty percent versus fifty percent versus zero percent?
Speaker 2: What does that look like?
Speaker 3: It's a great question. There are so many different mutations
Speaker 3: that you can have that I didn't even get into
Speaker 3: all of those specifics. But it's essentially just depends on
Speaker 3: what part of that gene is mutated and how big
Speaker 3: or like what type of mutation. That is to say,
Speaker 3: do you make any protein number one and number two?
Speaker 3: How well does that protein function or is it like
Speaker 3: a very misfolded protein that then our body just like
Speaker 3: cleans up as if you didn't make it. That makes sense, Yeah, yeah,
Speaker 3: So yeah, it's a it's a very big spectrum. But
Speaker 3: if we focus in on the more severe hemophilia, which
Speaker 3: I think is what we think of classically as hemophilia,
Speaker 3: then we can talk about the symptoms and know that
Speaker 3: if you have less severe disease, you would have less
Speaker 3: severe symptoms. So the symptoms, unsurprisingly are bleeding. This bleeding
Speaker 3: can be uncontrolled, it can be potentially life threatening. One
Speaker 3: of the hallmarks though, of where you get this bleeding
Speaker 3: is bleeding specifically into joint spaces. This is something called hemarthrosis.
Speaker 3: You can also get bleeding into muscle spaces. You can
Speaker 3: get potentially life threatening bleeding after a trauma or surgery.
Speaker 3: But one thing that is interesting about hemophilia A and B,
Speaker 3: unlike some other coagulopathies that affect other parts of the
Speaker 3: cascade or affect maybe platelet function, like that gum, you
Speaker 3: generally don't have severe or prolonged bleeding after minor cuts
Speaker 3: and scrape Okay, okay, why yeah, because the very first
Speaker 3: thing that happens when blood vessels are damaged is we
Speaker 3: put gum on them.
Speaker 2: Right, Okay, so they have platelet function, yeah, exactly.
Speaker 3: So for minor cuts and scrapes, you know, they're just
Speaker 3: getting your little capillaries in your blood. There's not a
Speaker 3: ton of flow. Platelets can do the job to stem
Speaker 3: that bleeding until repair happens.
Speaker 2: Okay.
Speaker 3: But larger, deeper blood vessels, like in our joint spaces,
Speaker 3: in our muscles, in our guts, in our liver, in
Speaker 3: your brain, these blood vessels have bigger flow, and you
Speaker 3: need platelets, and you need the entirety of the coagulation cascade,
Speaker 3: not just one arm of it. You need both arms
Speaker 3: to be able to stem that bleeding.
Speaker 2: Gotcha, and how early does this show up?
Speaker 3: Great question, very good question. Often after the first year
Speaker 3: of life, once a kid is walking and moving on
Speaker 3: their own. Okay, it certainly can happen before that, but
Speaker 3: very often it's after the first year of life, once
Speaker 3: kids are more mobile, and then what you often see,
Speaker 3: really the most common thing is bleeding into these joint spaces.
Speaker 2: Which sounds hugely painful.
Speaker 3: It's hugely painful. This can happen even without any preceding
Speaker 3: trauma or just minor trauma. It's what we call a
Speaker 3: spontaneous hemarthrosis, because anyone can bleed into their joint space
Speaker 3: with enough trauma. But these are massive bleeds that occur
Speaker 3: with no trauma, and like you said, they can be
Speaker 3: incredibly painful. They can also limit joint motion because our
Speaker 3: joints only have so much room in them to accumulate blood.
Speaker 3: But what's really bad about these is that blood is
Speaker 3: also very inflammatory. So even as the bleeding eventually slows
Speaker 3: and stops, because you have like the other arm of
Speaker 3: that coagulation cascades, like eventually you'll stop the bleeding, but
Speaker 3: you then trigger intense inflammation in that joint space because
Speaker 3: of the blood that's accumulated, which can then lead to sinovitis,
Speaker 3: which is inflammation of the connective tissue in the joints.
Speaker 3: That is very painful in itself, but it also can
Speaker 3: increase the likelihood of additional bleeding into the joint space
Speaker 3: because that area is inflamed. So it's this vicious cycle.
Speaker 3: Yeah yeah, and this can and often does lead to
Speaker 3: permanent disability because of these effects on the joints, So
Speaker 3: that's bad number one. Yeah, a similar process can happen
Speaker 3: in muscles. However, muscles, on the one hand, have more
Speaker 3: space in them, but large hemorrhages into muscles have the
Speaker 3: potential to compress other vital structures, so that can lead
Speaker 3: to things like nerve damage or other blood vessel obstruction,
Speaker 3: which can lead to like compartment syndrome, which is where
Speaker 3: you block off the blood flow to areas of your
Speaker 3: body because of that swollen muscle, and that's an emergency.
Speaker 3: And then of course hemophilia can also lead to death
Speaker 3: directly because of these hemorrhages, whether it's in the gut
Speaker 3: or the liver, but especially in the brain. So intracranial
Speaker 3: bleeds bleeds from blood vessels in the brain. I think,
Speaker 3: in before there was any treatment available, accounted for about
Speaker 3: twenty five percent of deaths in people with hemophilia.
Speaker 2: Oh my gosh.
Speaker 3: Yeah, And again most of these are happening without any
Speaker 3: preceding trauma, right, right, So if you understand that hemophilia
Speaker 3: is just a disruption in the way that our blood
Speaker 3: would normally clot, in the way that our blood has
Speaker 3: to clot, then it's just an inability for us to
Speaker 3: sufficiently duct tape our leaky pipes. Right, All of our
Speaker 3: blood vessels probably break and bleed at one point or
Speaker 3: another in our lives, Like you bonk your knee gently
Speaker 3: on a table, or you trip and fall down a
Speaker 3: flight of stairs, or you're a kid and you just
Speaker 3: ran and jumped off of a table just for fun. Right,
Speaker 3: Without the ability to quickly duct tape and patch those leaks,
Speaker 3: you get this uncontrolled bleeding. That's what hemophilia is, right,
Speaker 3: And there's no opportunity for the actual like healing and
Speaker 3: repair exactly right. But it is important to know that
Speaker 3: whether you're talking about heemophilia A or hemophilia B or
Speaker 3: some other coagulapathy. There's a very wide range of severity because,
Speaker 3: like I said already, even though this is a genetic disorder,
Speaker 3: it's not one single mutation, So there is a really
Speaker 3: wide range. And some people might not have any of
Speaker 3: these symptoms, but might, you know, as an adult bleed
Speaker 3: a lot after a tooth extraction and then later find out,
Speaker 3: oh I have low levels of factor eight or whatever.
Speaker 3: So yeah, that's that's hemophilia.
Speaker 2: Okay, Yeah, I feel like this was fairly straightforward.
Speaker 3: Right, It's pretty like if you understand that coagulation is
Speaker 3: a cascade of series of events, hemophilia is just taking
Speaker 3: out one or two of those factors.
Speaker 2: Yeah, I mean, and that also makes the treatment somewhat
Speaker 2: fairly straightforward as well. Does to an extent asterisk okay risk.
Speaker 3: Yeah, there is treatment, and we'll talk a little bit
Speaker 3: more about the kind of new ways that we do
Speaker 3: treatment now in the current events section. But one of
Speaker 3: the problems because we can essentially replace these factors, right,
Speaker 3: we know what these proteins are, we can just replace
Speaker 3: them in people's bodies. The factors don't last that long,
Speaker 3: so it requires a lot of IVY infusions. Also, anytime
Speaker 3: that you introduce something into the body like repeatedly, that's
Speaker 3: especially that's a blood factor, then make antibodies against it,
Speaker 3: and so you can end up with what are called
Speaker 3: inhibitors against these factors. So then the treatment becomes less effective.
Speaker 2: Right, But don't.
Speaker 3: Worry, there's good news on the horizon. We'll talk more
Speaker 3: about it later in the episode, but first, Aaron, can
Speaker 3: we go over I know the history of this is massive,
Speaker 3: so I can't wait to hear about it.
Speaker 2: Okay, I will dive in as soon as we take
Speaker 2: a short break. Yes, hemophilia has a huge and fascinating history,
Speaker 2: and it's one that includes a complete transformation from an
Speaker 2: acute disease to one that's chronic. It involves themes of
Speaker 2: gender and why public perception of disease matters, what it
Speaker 2: means to be quote socially creditable, the quest for state
Speaker 2: sponsored healthcare, and how pharmaceutical companies can play a nuanced role,
Speaker 2: often as both saviors and villains.
Speaker 3: Ooh, I'm excited already.
Speaker 2: Yeah. And if you learned about heemophilia before it was
Speaker 2: likely or possible in your intro bio or intro genetics
Speaker 2: class or something, and in that context, maybe you learned
Speaker 2: about sex link traits or how to draw pedigree. But
Speaker 2: I'm going to go into a lot more than that,
Speaker 2: and so I'm just gonna begin.
Speaker 3: I can't wait.
Speaker 2: Hemophilia is an ancient, ancient disease, as are a lot
Speaker 2: oftic diseases, right, It's probably always existed in humans since
Speaker 2: it happens from like you mentioned, many different mutations and
Speaker 2: can happen in so many different places as well that
Speaker 2: there are many different ways in which a clotting disorder
Speaker 2: can manifest, and this is also not unique to humans.
Speaker 2: It can of course affect other animals like dogs, which
Speaker 2: has actually been helpful in a number of ways since
Speaker 2: there are then appropriate animal models that you can use
Speaker 2: to study some of these different forms of humophilia. But
Speaker 2: not only has it probably always been around in humans,
Speaker 2: humans have also noticed it for a very long time.
Speaker 2: The earliest known references to bleeding disorders come from the
Speaker 2: Talmud from the second century CE, where it was written
Speaker 2: that male siblings are exempted from circumcision in cases where
Speaker 2: other male siblings in that family have died from the
Speaker 2: ritual yep, and there are other things like that in
Speaker 2: terms of like regulations or advisements, and throughout the medieval
Speaker 2: period there are additional mentions or descriptions of fatal bleeding disorders,
Speaker 2: but the real history of this disease doesn't begin really
Speaker 2: until the eighteen hundreds, and even then it's I would
Speaker 2: describe it as fairly light until the twentieth century, which
Speaker 2: for me, or at least like the late eighteen hundreds,
Speaker 2: which for me, totally goes against what I had, you know,
Speaker 2: had of this perception of hemophilia before doing this episode.
Speaker 3: I also assumed it would be super ancient.
Speaker 2: Yeah, I mean, and it very much is. But in
Speaker 2: terms of like the big changes that have happened, most
Speaker 2: of them are in the twentieth century.
Speaker 3: Yeah.
Speaker 2: So, anyway, going back to the eighteen hundreds, in eighteen
Speaker 2: oh three, a physics from Philadelphia named John Conrad Otto
Speaker 2: published a paper on hemophilia titled quote an Account of
Speaker 2: a Hemorrhagic Disposition Existing in certain Families, which was not
Speaker 2: necessarily the first article on what would later become known
Speaker 2: as hemophilia, which Auto actually called a hemorrhagic idiosyncrasy, but
Speaker 2: it has been held as the first important description for
Speaker 2: a number of reasons. One is that it noted the
Speaker 2: familial nature of the disease and the fact that males
Speaker 2: tended to be affected. Quote, it is a surprising circumstance
Speaker 2: that the males only are subject to the strange affliction,
Speaker 2: and that all of them are not liable to it.
Speaker 2: Although the females are exempt, they are still capable of
Speaker 2: transmitting it to their male children.
Speaker 3: I kind of love heemorrhagic disposition.
Speaker 2: Hemorrhagic idiosyncrasy, hemorrhagic disposition.
Speaker 3: Yeah, Yeah, interesting, interesting title it is.
Speaker 2: Yeah. And then the second reason that it was this
Speaker 2: important description is that it kind of got the word
Speaker 2: out there and sparked interest in this disease in both
Speaker 2: the rest of the US and across Europe. And finally,
Speaker 2: it described the disease not just as a curiosity, but
Speaker 2: as something that was in need of effective treatments to
Speaker 2: manage bleeds. Consider the state of medicine in the US
Speaker 2: at this time, right early eighteen hundreds. Treatments or medicines
Speaker 2: were rarely useful. Most of them were just like a strong,
Speaker 2: gross cocktail full of mysterious ingredients and like beef liver
Speaker 2: or something, and bleeding was a very common treatment still.
Speaker 3: So I was just going to say blood leding.
Speaker 2: Blood letting. Yeah, and so you can imagine that this
Speaker 2: would be a very bad idea for somebody with hemophilia.
Speaker 2: And naturally the family that this physician Auto described in
Speaker 2: his account, they were all very against being bled and
Speaker 2: had actually stopped seeking out cures from doctors rather almost
Speaker 2: like instructing the physicians themselves on how they manage the
Speaker 2: bleeds and what they had found to be effective.
Speaker 3: Interesting.
Speaker 2: Yeah, So after Otto's account was published, physicians who read
Speaker 2: it began to think, Oh, I've seen something like this before,
Speaker 2: or huh, this sounds a lot like a patient that
Speaker 2: I currently have. And so from this point on there
Speaker 2: was sort of the slow momentum of gathering more data
Speaker 2: on disease signs and symptoms, how bleeds occurred, diagnosis, any
Speaker 2: possible treatments which there weren't any. Right, And while the
Speaker 2: disease remained hot for a while in the US, where
Speaker 2: it mostly picked up traction was in Germany, where the
Speaker 2: disease had become fairly well known during the early decades
Speaker 2: of the eighteen hundreds. And Germany was also where formal
Speaker 2: metic training and this high prevalence of hospitals is allowed
Speaker 2: for more data collection and also central places with a
Speaker 2: high volume of people going through So you just have
Speaker 2: more frequency of people with hemophilia.
Speaker 3: Right, just because there's more humans there, exactly. Yeah.
Speaker 2: So, around the mid eighteen hundreds, hemophilia had earned a
Speaker 2: clinical definition, essentially that it was quote inherited tendency in
Speaker 2: males to bleed and also a name which you described earlier.
Speaker 2: And despite the progress though made by the mid to
Speaker 2: late eighteen hundreds on the prevalence of hemophilia or in
Speaker 2: clinical descriptions of the disease, there was really no meaningful
Speaker 2: improvement on treatment or management during this time. There was
Speaker 2: a physician in Germany, Ludwig Grandidier, I don't know how
Speaker 2: you say it, who helped to spread a uniform understanding
Speaker 2: of this disease throughout Europe, and he also compiled stats
Speaker 2: on hemophilia and life expectancies which were extremely grim. So,
Speaker 2: just to put a number to it, more than fifty
Speaker 2: percent of the people with hemophilia that he documented ended
Speaker 2: up dying before they were eight years old, Oh my god.
Speaker 2: And of those that did survive past eight, only twelve
Speaker 2: percent made it past their twenty first birthday.
Speaker 3: Oh my gracious.
Speaker 2: So it's really really bad. So all right, but I
Speaker 2: want to now at this point we've gone through most
Speaker 2: of the eighteen hundreds, and so I want to kind
Speaker 2: of just situate ourselves a bit with the timing of
Speaker 2: this and other research. So in the late eighteen hundreds,
Speaker 2: this is the period when diseases began to be described quantitatively, right,
Speaker 2: when doctors sought a consensus on appropriate treatments, when there
Speaker 2: was a lot more publication and wide sharing of information,
Speaker 2: when stats began to be used in medicine. And also
Speaker 2: if you think back to our Huntington's Disease episode, it's
Speaker 2: also when genetics began to be used to declare who
Speaker 2: should or shouldn't be reproducing, aka eugenics. Eugenics Aaron, do
Speaker 2: you remember when you first learned about hemophilia, Like in
Speaker 2: what context?
Speaker 3: It probably was in whatever intro bioclass went over genetics.
Speaker 2: Right, yeah, yeah, same for me, it was I think
Speaker 2: it was like genetics or intro bio. It was used
Speaker 2: as this classic example, this archetypal example of a sex
Speaker 2: link trait and learning how to trace inheritance by drawing
Speaker 2: out a pedigree, like I'm pretty sure it was on
Speaker 2: a test.
Speaker 3: YEP, definitely yeah.
Speaker 2: And it turns out that it has actually been used
Speaker 2: this way for ages as a way to teach Mendelian
Speaker 2: genetics and sex linked inheritance to the general public, and
Speaker 2: it was especially used around the late eighteen hundreds and
Speaker 2: early nineteen hundreds, also as a way to illustrate how
Speaker 2: bad genes could be passed through generations, often with the
Speaker 2: explicit suggestion that quote bleeders should be prohibited from reproducing. Often, though,
Speaker 2: eugenesists argued that men with hemophilia should be allowed to
Speaker 2: marry because their sons would not be affected, but that
Speaker 2: the daughters should then be prohibiting from reproducing. Just infuriating,
Speaker 2: of course, and this suggestion taps into a couple of
Speaker 2: the themes of this disease. One is this historically gendered perception.
Speaker 2: For the longest time, it was thought that only males
Speaker 2: could have hemophilia, and being male was real requirement for
Speaker 2: a diagnosis. Women who presented with a bleeding disorder were
Speaker 2: often diagnosed with like parahemophilia or something to that effect,
Speaker 2: not real hemophilia, but something that looks a lot like it,
Speaker 2: and a lot of the language that was used to
Speaker 2: describe women with a hemophilia allele was pretty accusatory even
Speaker 2: once eugenics died down, and the boys with the disease
Speaker 2: were often portrayed as not having or being able to
Speaker 2: have masculine traditionally masculine traits, am using masculine quotes, you know,
Speaker 2: being able to run around and play rough and climb
Speaker 2: trees and shoot guns or whatever it is that was,
Speaker 2: you know, masculine, and this gendered perception of hemophilia, where
Speaker 2: hemophilia in a way was like making you less masculine.
Speaker 2: And then the ideal, the quest for normality meant being
Speaker 2: able to, you know, ride on a bike and I
Speaker 2: don't know, do wheelies. Yeah, to be a man. That's
Speaker 2: the only thing I could think of about bike riding.
Speaker 3: You have to do wheelis to be a man, and
Speaker 3: you have to be a man. That's what we've learned.
Speaker 2: Yeah, if you take one thing away from this episode is.
Speaker 3: That girls definitely can't Papa wheelie.
Speaker 2: Definitely not, certainly not. And I never climbed a tree
Speaker 2: in my life. I never, no, But but yeah, this
Speaker 2: was sort of this predominant overshadow perception throughout a lot
Speaker 2: of the twentieth century, at least until our understanding of
Speaker 2: the disease became more nuanced, and the concept of you know,
Speaker 2: quote normality as the ideal to aspire towards that kind
Speaker 2: of fell out of favor. But the eugenical treatment of hemophilia,
Speaker 2: as well as this accusatorial language towards mothers of hiemophili sons,
Speaker 2: it led to a substantial amount of stigma surrounding hemophilia. Yeah,
Speaker 2: and while many eugenicists or geneticists in Europe and North
Speaker 2: America felt free to add to the stigma as much
Speaker 2: as they wanted by making recommendations on who should or
Speaker 2: shouldn't be allowed to reproduce, many physicians in England had
Speaker 2: to be a bit more restrained. And that's yeah, you
Speaker 2: know why because the pedigree, right, that's because of Queen Victoria,
Speaker 2: who unknowingly passed along the hemophilia alile she was actually
Speaker 2: in denial about it to three of her children, her
Speaker 2: son Prince Leopold, and two daughters, Alice and Beatrice. In
Speaker 2: this story, this passing of the hemophilia aliele to several
Speaker 2: of her children and then several of her grandchildren led
Speaker 2: to hemophilia getting the nickname. Of course, the royal disease.
Speaker 2: So rather than taking this eugenic stance, the prevalence of
Speaker 2: the disease in the royal family and the descendants led
Speaker 2: British physicians to instead focus more on treatment and management.
Speaker 2: And it also in a way, just like overall, increased
Speaker 2: this interest in the disease.
Speaker 3: It's so interesting, Aaron.
Speaker 2: And speaking of interesting things about this disease, the presence
Speaker 2: of hemophilia in descendants of Queen Victoria led to one
Speaker 2: of the most frequently mentioned anecdotes about the disease, and
Speaker 2: that is of Resputant and the last Russian imperial family.
Speaker 2: I could spend the whole episode talking about just this
Speaker 2: because it is such a fascinating chapter of history. But
Speaker 2: I'm just going to go over this story briefly, and
Speaker 2: if you want more info, I highly highly recommend the
Speaker 2: book Nicholas and Alexandra by Robert Massey, who, by the way,
Speaker 2: was partially inspired to write it because his son, just
Speaker 2: like the last heir of the Russian throne, Alexei Romanov,
Speaker 2: had hemophilia. Okay, so Nicholas the second and Alexandra were
Speaker 2: the last Emperor Empress of Russia. Alexandra was the granddaughter
Speaker 2: of Queen Victoria, and she had inherited a copy of
Speaker 2: the Hymophilia Alile, which she passed down to her son, Alexei,
Speaker 2: who was the baby of five children and the only boy,
Speaker 2: and so he was the heir apparent to the Russian throne.
Speaker 2: And Nicholas and Alexandra became aware of their son's disease
Speaker 2: pretty early in his life, which, as you mentioned, is
Speaker 2: often the case, and they went through great efforts to
Speaker 2: protect their son from any injury that could prove deadly
Speaker 2: and also to conceal his disease to the public, and
Speaker 2: he figuring in some pretty horrific bleeds, as she has
Speaker 2: in a lot of her letters, Alexandra, they still exist
Speaker 2: and it's just like heartbreaking, the amount of pain I
Speaker 2: can't imagine. And around this time, in the early nineteen hundreds,
Speaker 2: treatments for the disease were still nonexistent and doctors had
Speaker 2: actually started to use aspirin often, which only made the
Speaker 2: bleeds worse. And Alexandra, who of course cared deeply about
Speaker 2: her son's safety and also as the Empress, knew that
Speaker 2: part of her value was wrapped up in producing an
Speaker 2: air to the throne and getting him to adulthood. She
Speaker 2: did everything in her power to keep Alexi alive, including
Speaker 2: reaching out to a faith healer by the name of
Speaker 2: Grigory Resputin Resputin Rasputin, who had promised to keep Alexi safe.
Speaker 2: Alexandra and Nicholas, they were desperate for their sol well
Speaker 2: being and that made them utterly loyal to Resputant, afraid
Speaker 2: of upsetting him and losing his healing powers, which were
Speaker 2: I mean yeah, and Resputant completely took advantage of this.
Speaker 2: He demanded that they appoint ministers of his choosing, kick
Speaker 2: out the ones that weren't his, that weren't a fan
Speaker 2: of his. He wanted to be informed of any army
Speaker 2: movements during World War One, and basically he just wanted
Speaker 2: to have complete freedom to do whatever he wanted and
Speaker 2: not lose any power. And their reliance on Resputant, their
Speaker 2: utter loyalty blind loyalty to him led to ultimately a
Speaker 2: lot of discontent among the Russian people, and it led
Speaker 2: to the February Revolution of nineteen seventeen, when the monarchy
Speaker 2: was abolished and the royal family, after a period of exile,
Speaker 2: was executed, including Alexi and Anastasia. Despite what the animated
Speaker 2: movie might have led you.
Speaker 3: Yeah, that's my only reference point for that whole story.
Speaker 3: By the way, is.
Speaker 2: I feel like the movie fairly accurately portrayed Resputin as
Speaker 2: a real creep, because he really was, and the pictures
Speaker 2: of him are utterly terrifying. Yeah, and the whole story
Speaker 2: I think is just like even more deeply fascinating and
Speaker 2: heartbreaking too, because this like poor little boy had the
Speaker 2: weight of the world on his shoulders and whatever. And
Speaker 2: there's also a lot of really interesting discussions on what
Speaker 2: would have happened if Alexi hadn't had hymophilia and how
Speaker 2: history might have played out differently. And I find all
Speaker 2: that super interesting, and again read the book Nicholas and
Speaker 2: Alexandra for more on that. It's great, But as much
Speaker 2: as I would love to discuss hypothetical alternative histories, instead
Speaker 2: going to move back to solid to see how things
Speaker 2: changed for people with hemophilia in the twentieth century. Eventually,
Speaker 2: early on, the eugenicists were silenced, in part because eugenics
Speaker 2: was starting to fall out of favor, and also because
Speaker 2: they realized that their plans for large scale sterilization weren't
Speaker 2: practical For hemophilia, they still performed plenty of sterilizations otherwise
Speaker 2: because the rate of new mutations was so high, and
Speaker 2: so attention then turned more towards understanding the disease and
Speaker 2: the hopes that it would shed some light on possible treatments.
Speaker 2: So although the clinical definition of hemophilia was well recognized
Speaker 2: by the early nineteen hundreds, the path of physiological nature
Speaker 2: was less certain. Like all doctors knew was that bleeding
Speaker 2: was difficult to stop. What step They didn't even have
Speaker 2: a cascade yet, like they had no idea. Many doctors
Speaker 2: had hypothesized that it was actually due to heart malformation
Speaker 2: or a degenerative blood vessels, or maybe even a spleen abnormality.
Speaker 2: And this was like in the early days, it was
Speaker 2: just a constitutional deficiency, like, oh, you have a weak constitution,
Speaker 2: like you're in a Jane Austin novel or something.
Speaker 3: Yeah.
Speaker 2: Yeah. But a big breakthrough came in eighteen ninety three
Speaker 2: when bacteriologist Almroth Edward Wright, who has made an appearance
Speaker 2: on the podcast before, I think in the second Vaccines
Speaker 2: episode and in our Typhoid episode. He was a big
Speaker 2: vaccine guy.
Speaker 3: You have a good memory.
Speaker 2: Well, so actually what I did. I was like, that
Speaker 2: name sounds familiar, and then I went to our folder
Speaker 2: and I typed in Almroth Edward Wright, and I looked
Speaker 2: in the mates from the past episodes. So this guy, though,
Speaker 2: observed that the average clotting time for a child with
Speaker 2: hemophilia was two to three times longer than it took
Speaker 2: for his own blood to clot And this was a
Speaker 2: big deal because not only did it open the door
Speaker 2: a bit for a diagnosis, even though clotting times was
Speaker 2: a pretty crude method and not the most reliable, but
Speaker 2: it also showed that the disease was a clotting disorder, right,
Speaker 2: it wasn't a heart malformation or whatever else. And that
Speaker 2: also meant that if you could treat the clotting, you
Speaker 2: could potentially treat the disease, possibly by adding substances that
Speaker 2: helped clot or more practically, through blood transfusions. But if
Speaker 2: you remember from our Hepatitis C episode where I talked
Speaker 2: a lot about the history of blood transfusions, they were
Speaker 2: by no means routine or remotely safe in the early
Speaker 2: nineteen hundreds, not at all, and there was still a
Speaker 2: lot of lingering controversy from the previous sent or centuries
Speaker 2: really that had made them illegal actually in many places,
Speaker 2: which didn't mean they weren't performed though. If you remember,
Speaker 2: in eighteen forty, there was a transfusion performed on an
Speaker 2: eleven year old boy with hemophilia who was on death's
Speaker 2: door before receiving the blood. Somehow the transfusion worked and
Speaker 2: the boy lived, but it seemed to be an isolated
Speaker 2: attempt for at least the next seventy or so years,
Speaker 2: at least when it came to hemophilia. Starting in the
Speaker 2: early nineteen hundreds, hematology really began to grow as a field,
Speaker 2: and this then led to a resurgence in transfusion experiments.
Speaker 2: One of these was performed by surgeon Beth Vincent on
Speaker 2: a patient who had hemophilia, and this was in nineteen sixteen.
Speaker 2: I believe. Prior to the transfusion, the donor's clotting time
Speaker 2: was seven minutes and the recipient's one hundred and fifty minutes.
Speaker 3: Wow.
Speaker 2: Yeah, post transfusion that dropped down to eight minutes, so
Speaker 2: that was like, okay, there's some serious promise here. And
Speaker 2: additional experiments followed this one, but for the most part,
Speaker 2: transfusion science and hematology was not driven by research into hymophilia,
Speaker 2: but rather one the increased need and awareness that blood
Speaker 2: transfusions were capable of saving lives. That was especially demonstrated
Speaker 2: very clearly during World War One. Number Two, Another thing
Speaker 2: that drove hematology and transfusions was improvements in sterilization. Transfusions
Speaker 2: and pre germ theory. Days often failed just due to
Speaker 2: dirty needles, right. Number three. The discovery of blood types
Speaker 2: also really kind of helped shed some light on why
Speaker 2: transfusions failed or were successful, although that was really more
Speaker 2: than nineteen twenties and thirties and number for the addition
Speaker 2: of anticoagulants like sodium citrate or sodium phosphate. These really
Speaker 2: helped increase the life of donated blood. So it was
Speaker 2: sort of this step wise like, okay, it's just a
Speaker 2: little more info here, a little more info here, refining
Speaker 2: and you know, retooling until we have like a routine procedure.
Speaker 2: And while hemophilia was not a driving force or the
Speaker 2: reason necessarily for these improvements in transfusion technology, it would
Speaker 2: greatly benefit from them. And I also want to point
Speaker 2: out that many people with hemophilia played hugely important roles
Speaker 2: in some of these developments, both in terms of transfusion science,
Speaker 2: but also in terms of understanding the you know, nuanced disease,
Speaker 2: that is, all of these different hemophilias or different types
Speaker 2: of hemophilia, because without their involvement and their without their
Speaker 2: willingness to provide the blood samples or their time or
Speaker 2: their bodies for the study of different treatsments, it wouldn't
Speaker 2: have been possible to track down exactly what plotting factor
Speaker 2: was responsible for which disorder, and which treatments were effective,
Speaker 2: how much plasma to give and how often to give it, etc.
Speaker 2: By the mid twentieth century, the concept of hemophilia had
Speaker 2: undergone a dramatic change, due in large part to improvements
Speaker 2: in transfusions. At the beginning of the twentieth century, like
Speaker 2: I said, transfusions were still a rarity, and then World
Speaker 2: War Ones showcased the need for a reliable blood supply
Speaker 2: and better ways of getting it into someone. The years
Speaker 2: that followed that war improved upon that, and then transfusions
Speaker 2: really came into their own and became routine during World
Speaker 2: War II, which is also when blood banks were established
Speaker 2: and the concept of blood donation became widespread. Alongside all
Speaker 2: of these wider developments for the fields of hematology and
Speaker 2: transfusion science came this huge revolution inphilia. At the start
Speaker 2: of the century, it was viewed as an acute disease,
Speaker 2: and in practice it was. I mean, you heard the
Speaker 2: numbers that I cited from that German physician, right, it
Speaker 2: was hugely deadly. There were no effective treatments, and this
Speaker 2: life expectancy was dismal. But by the nineteen fifties, the
Speaker 2: availability of transfusions and growth in knowledge about the disease
Speaker 2: had turned hemophilia into a manageable chronic disease, a disease
Speaker 2: that you live with for years and years and years.
Speaker 2: The development of essays in the nineteen fifties for identification
Speaker 2: of clotting factors led to this much more nuanced understanding
Speaker 2: of bleeding disorders overall. And this also drew into question
Speaker 2: the historical assumption that there had to be a family
Speaker 2: history of bleeding, or that the person had to be male,
Speaker 2: had to have just one X chromosome.
Speaker 3: Yeah, that's important because I didn't even mention that, but
Speaker 3: like one third of all hemophilia is a new mutation. Wow,
Speaker 3: it's one third one third. Yeah, So just because there's
Speaker 3: no family history, doesn't mean much.
Speaker 2: That's like, that's much higher than I realized. Wow. Yeah,
Speaker 2: So yeah, hemophilia was turning out to be and has
Speaker 2: turned out to be, not quite the straightforward disease that
Speaker 2: it had always been thought to be.
Speaker 1: Right.
Speaker 2: But just as the disease had begun its transformation from
Speaker 2: acute to chronic, the blood supply began to dwindle after
Speaker 2: donations slowed once World War Two ended and there was
Speaker 2: no longer that patriotic push to donate for the soldiers
Speaker 2: on the front line, right, Yeah, And so what happened
Speaker 2: was that people with hemophilia came together to form advocacy
Speaker 2: groups and organizations such as the National Heemophilia Foundation NHF
Speaker 2: to raise awareness about the disease and need for blood donations,
Speaker 2: to put the need for blood in perspective. I'm gonna
Speaker 2: cite one very widely reported case, and it's definitely an outlier,
Speaker 2: but I do think it is sort of eye opening.
Speaker 2: So there's a thirty one year old person with hemophilia
Speaker 2: who received a record two hundred and thirty two pints
Speaker 2: of whole blood and one hundred and sixty eight pints
Speaker 2: of plasma while bleeding continuously for four hundred and twenty
Speaker 2: two hours. Oh my, yeah, it's a lot of blood.
Speaker 3: It's an unbelievable amount. Like I don't even know how
Speaker 3: many times of a human volume of blood you've replaced
Speaker 3: that a lot?
Speaker 2: Yeah, Yeah, And the sad part is that unfortunately this
Speaker 2: person did not make it. But the high publicization of
Speaker 2: this case highlighted the enormous need that a lot of
Speaker 2: people with hemophilia faced, And there were many other publicized
Speaker 2: stories of people with hemophilia around the time that had
Speaker 2: this overarching message of you know, people with humophilia can
Speaker 2: live a quote normal life if they have access to
Speaker 2: blood and or plasma. And these stories were powerful in
Speaker 2: that they garnered a lot of support for blood drives,
Speaker 2: but they also kind of drew on the old stigma
Speaker 2: of someone with hemophilia being sickly and vulnerable, always reliant
Speaker 2: on the generosity of others. And it's kind of like
Speaker 2: this paradox where this increased visibility and having to showcase
Speaker 2: the challenges of living with hemophilia was the only way
Speaker 2: to ensure a quote normal life and not having to
Speaker 2: live with the challenges of humophilia.
Speaker 4: Yeah, it's just an interesting sort of position to be in,
Speaker 4: I think and groups like the NHF, the National Hemophilia Foundation,
Speaker 4: they were a huge step in forming a community where
Speaker 4: people could share information and connect over their experiences, and
Speaker 4: it was also certainly a case of strength and numbers.
Speaker 2: By forming these national groups, people with hemophilia could amplify
Speaker 2: their voices and advocate for themselves or their children, for
Speaker 2: improvements in hematological technology, for public assistance for families affected
Speaker 2: by the disease, because transfusions were very expensive and could
Speaker 2: be very disruptive to routine life right like school, for instance,
Speaker 2: and many of these efforts paid off. The nineteen sixties
Speaker 2: saw the continued transformation of hemophilia into a manageable disease,
Speaker 2: and that was especially helped along by technological advancements like
Speaker 2: plasma paresis, which allowed people to donate plasma more frequently
Speaker 2: and cryo precipitate, which allowed for the concentration of particular
Speaker 2: clotting factors and was much more potent than fresh plasma
Speaker 2: in stopping bleeds. And while cryo had some pretty big
Speaker 2: advantages over plasma, like increased autonomy with home administration and
Speaker 2: quicker access, it still had some drawbacks. Many physicians didn't
Speaker 2: allow their patients to administrate at home, and if you
Speaker 2: were experiencing a bleed, you still had to wait to
Speaker 2: have it fall and endure that horrific pain as you waited,
Speaker 2: and there were still issues with shortages. The real dream
Speaker 2: was in clotting factor concentrates, a dream that would be
Speaker 2: realized in the late nineteen sixties when factor eight concentrate
Speaker 2: first became commercially available, sourced from for profit plasma centers,
Speaker 2: which had less of a supply issue than those that
Speaker 2: were strictly volunteer. The development of factor eight and other
Speaker 2: clotting factors had vastly improved the quality of life and
Speaker 2: the health status of many people with hemophilia, and the
Speaker 2: leading voices in these hemophilia advocacy groups were increasingly those
Speaker 2: of the people with hemophilia themselves rather than their parents,
Speaker 2: as they were living to be older and older, and
Speaker 2: one thing became very clear. While cryo and clotting factors
Speaker 2: were incredibly effective at managing hemophilia, they were also incredibly expensive.
Speaker 2: And this wasn't a one time expense, right, This was
Speaker 2: a chronic disease. This was years of weekly or monthly costs,
Speaker 2: and the conversation then turned towards medical care as a
Speaker 2: right rather than a commodity, as clotting factor as a
Speaker 2: rite rather than a commodity, and hemophilia advocacy groups in
Speaker 2: the US. And this, most of this history, I forgot
Speaker 2: to say, is focused on the US, because that's where
Speaker 2: the book that I read and got a lot of
Speaker 2: this is largely from. And the history is already enormous
Speaker 2: as it is. But I do want to note that
Speaker 2: many other countries in Europe, the clouding factors were paid
Speaker 2: for by the state already, no question, right, They didn't have.
Speaker 3: To form an organization to fight for it.
Speaker 2: It was sorry, right, right, yeah, And so but these
Speaker 2: advocacy groups, that wasn't the case in the US. So
Speaker 2: these advocacy groups there began to demand comprehensive care programs
Speaker 2: for people with hemophilia, like not just paying for the
Speaker 2: clouding factors, but also helping to pay for all of
Speaker 2: the struggles around this as well, right, like helping with schooling,
Speaker 2: helping transportation, et cetera. During this time, Nixon was President
Speaker 2: of the US, and his policy was superficially to have
Speaker 2: more health coverage, when in reality it absolutely wasn't. It
Speaker 2: was cut down in so many areas that created this
Speaker 2: massive competition both among different government agencies and also across
Speaker 2: different disease support groups to determine which disease was worthy
Speaker 2: of support, right Like, each group had to advocate for
Speaker 2: themselves like no, I'm worthy, No I'm more worthy, And
Speaker 2: in this case, the hemophilia advocacy groups did have a
Speaker 2: bit of a leg up. First of all, they had
Speaker 2: been working in the public eye for almost two decades
Speaker 2: by that point, raising awareness about the disease and then
Speaker 2: pushing for these blood donations. And secondly, with the development
Speaker 2: of clotting factors and other plasma treatments, they had established
Speaker 2: themselves as consumers, right because they still weren't having these
Speaker 2: things subsidized, and that status as consumers gave them more, say,
Speaker 2: especially with Nixon gross I know. And thirdly was public perception.
Speaker 2: People with humophilia were often portrayed a as quote socially creditable,
Speaker 2: as in, you know, with access to treatment, they could
Speaker 2: be productive members of society and live quote normal lives,
Speaker 2: and so they deserved more funding than those viewed as
Speaker 2: hopeless causes, right.
Speaker 3: Right, Yeah, I feel like we talked about this in
Speaker 3: a few other episodes.
Speaker 2: I was just yeah, I was just going to say,
Speaker 2: we've talked about how public perception of diseases and especially
Speaker 2: how the demographic of the people who are most affected
Speaker 2: by diseases, how those things play a big role in
Speaker 2: the amount and type of funding that a disease gets.
Speaker 2: And the author of this book that I read argues
Speaker 2: that this, you know, socially creditable status was a big
Speaker 2: factor in getting a comprehensive care bill successfully passed in
Speaker 2: nineteen seventy five that subsidized programs for people with hemophilia
Speaker 2: in the US. So by the mid to late nineteen seventies,
Speaker 2: things were looking up right. Doctors were now advocating for
Speaker 2: at home transfusions or concentrate injections, which had greatly increased
Speaker 2: the autonomy of people with hemophilia. There were improvements in
Speaker 2: treatments that were always happening, and for many people with hemophilia,
Speaker 2: the state sponsored financial support was helping to manage their healthcare.
Speaker 3: But I know what this butt is and it's just
Speaker 3: so awful.
Speaker 2: It is really horrible. Yeah, these improvements, all of this
Speaker 2: progress was soon going to be mostly undone by a
Speaker 2: global public health crisis, one to which people with hemophilia
Speaker 2: were especially vulnerable. HIV AIDS yeah in nineteen eighty two,
Speaker 2: the CDC received a report of a sixty two year
Speaker 2: old man with hemophilia who had died from numicis to steumonia,
Speaker 2: which usually doesn't cause death except in immuno compromised individuals.
Speaker 2: In this numisicististemonia case, this was part of a larger
Speaker 2: alarming trend of outbreaks of these opportunistic pathogens killing people
Speaker 2: who had been healthy. Just months before the report of
Speaker 2: this man with hemophilia dying of pneumsistas pneumonia set off
Speaker 2: alarm bells at the CDC and made the hematologist there
Speaker 2: think that whatever was causing this outbreak of what immune syndrome,
Speaker 2: it might be bloodborn and additional cases of this emerging
Speaker 2: immune syndrome and other people with hemophilia fur their support
Speaker 2: of the blood born pathogen hypothesis, and it suggested to doctors,
Speaker 2: especially doctors of people with haemophilia, that there were going
Speaker 2: to be many more on the horizon. Despite this, the
Speaker 2: risk to people receiving blood transfusions, not just people with hemophilia,
Speaker 2: but anyone who would receive a blood transfusion. It was
Speaker 2: frequently downplayed in the early months of the AIDS crisis,
Speaker 2: or even in the early year and in part because
Speaker 2: it was simply not known how long the course of
Speaker 2: disease was, how long the incubation time was, and also
Speaker 2: because the hemophilia community had been fighting for so long
Speaker 2: for these life saving treatments and for access reliable access
Speaker 2: to them. And it also must be said that part
Speaker 2: of the reason it was downplayed was probably because of
Speaker 2: the commercial interests of these blood and plasma banks or
Speaker 2: pharmaceutical companies making these blood derived products. Yeah, definitely, it
Speaker 2: is horrifying in retrospect to read this statement, for example
Speaker 2: from the National Hemophilia Foundation in nineteen eighty two quote,
Speaker 2: the risk of contracting this immunis depressive agent is minimal
Speaker 2: and CDC is not recommending any change in blood product use.
Speaker 2: At this time, the blood borne hypothesis started out controversial,
Speaker 2: and many organizations demanded more solid studies before any policy
Speaker 2: changes were made regarding the blood supply. Eventually, additional cases
Speaker 2: in nineteen eighty two showed that the pathogen could be
Speaker 2: transmitted through blood, but the causative agent was still unknown
Speaker 2: at this time, so there was no way to screen
Speaker 2: the blood against it. Alternatives to screening were proposed, such
Speaker 2: as barring quote high risk individuals from donating or screening
Speaker 2: for hepatitis B as a surrogate, since there was a
Speaker 2: high correlation between BEE prevalence and this unknown immune syndrome.
Speaker 2: And the controversy surrounding these decisions is part of a
Speaker 2: much larger conversation, and it's one that we touched on
Speaker 2: a bit in our HIV AIDS episode from our first season,
Speaker 2: and it's been cover in depth and many books and
Speaker 2: articles elsewhere where they would do a much better job
Speaker 2: than I would ever do, so I'm not going to
Speaker 2: go into it here. But the result of many of
Speaker 2: these decisions, the delay in action and policy, the type
Speaker 2: of decision that was made, the denial that many blood
Speaker 2: bank organizations and plasma companies expressed that their blood supply
Speaker 2: could be dangerous. The result of all of this was
Speaker 2: that many, many people with hemophilia became infected with HIV,
Speaker 2: even after blood bank testing for the virus began in
Speaker 2: nineteen eighty five.
Speaker 3: Oh, it's really interesting, Aaron, because this is a huge
Speaker 3: part of the hemophilia story, right, But I don't remember
Speaker 3: ever learning it when I learned about hemophilia, when I
Speaker 3: learned about HIV, when I learned about even heps.
Speaker 2: I remember learning about it in HIV in the context
Speaker 2: particularly of Ryan Way and who I'll talk about I'll
Speaker 2: touch on in a minute, and in hepsie also because
Speaker 2: it was a big problem. And that's sort of like
Speaker 2: one of the themes here is that this should not
Speaker 2: have been that much of a surprise in a number
Speaker 2: in a certain way, right because the increased susceptibility to
Speaker 2: blood borne pathogens for people with hemophilia, this was well known.
Speaker 2: The term canary in the coal mine has often been used,
Speaker 2: and that does imply a bit of like intent in
Speaker 2: some ways, and I'm not sure if it's like the
Speaker 2: most appropriate term, but it is true that there have been,
Speaker 2: you know, even back in the nineteen seventies, extremely high
Speaker 2: rates of hepatitis B, like over fifty percent in people
Speaker 2: with hemophilia, and also hepatitis C. Those are what they
Speaker 2: had called at the time, non A non be hepatitis.
Speaker 2: Those had been observed at least starting in the seventies,
Speaker 2: But what was often the case was that these infections
Speaker 2: they were often viewed by physicians as sort of the
Speaker 2: lesser of two evils, and some did not even disclose
Speaker 2: the infection to their patients. Oh goodness, right, And so
Speaker 2: then when there was the switch to clotting factor concentrates,
Speaker 2: especially using pulled human plasma, So like one lot of
Speaker 2: this of these clotting factor concentrates could have plasma from
Speaker 2: ten thy to twenty thousand individuals, and so hepatitis B
Speaker 2: in C cases soared. At that point, one person infected
Speaker 2: with one of those pathogens who had donated plasma, that
Speaker 2: could lead to that entire lot testing positive. So in
Speaker 2: the context of this pooled clotting factor concentrates and sort
Speaker 2: of the unwillingness of some doctor to sound the alarm
Speaker 2: or the inaction whatever, it might not be surprising, but
Speaker 2: it is still horrifying to learn that by nineteen ninety four,
Speaker 2: more than twenty five percent of people with hemophilia in
Speaker 2: the US had died of causes related to AIDS, and
Speaker 2: an overwhelming majority of people with hemophilia had contracted the virus.
Speaker 2: Of the eight thousand people with severe heemophilia in the
Speaker 2: US in the early nineteen eighties, nearly ninety percent would
Speaker 2: acquire HIV, and their partners often became infected as well,
Speaker 2: with many dying also. The AIDS crisis once again put
Speaker 2: people with hemophilia in the public eye. One of the
Speaker 2: most famous was Ryan White, who I mentioned before. This
Speaker 2: was a boy a young boy from Cocomo, Indiana, who
Speaker 2: had been kicked out of school by parents who were
Speaker 2: afraid for their kids after he tested positive for HIV. Ryan,
Speaker 2: like many other people with chemophilia, he went on talk
Speaker 2: shows to raise awareness about humophilia and HIV and also
Speaker 2: was attempting to reduce some of the stigmatization of HIV
Speaker 2: and AIDS. Unfortunately, Ryan White died in nineteen ninety and
Speaker 2: much of the stigma both towards people with hemophilia, who
Speaker 2: were viewed as quote innocent victims, as well as other
Speaker 2: people with HIV. This stigma persisted and continues to persist.
Speaker 2: Of course, the spread of HIV changed so much of
Speaker 2: the landscape for people with hemophilia, and not just in
Speaker 2: the extremely high prevalence of infection. Many doctors didn't properly
Speaker 2: inform their patients about the risks of concentrates from large pools,
Speaker 2: and many people didn't listen to their doctor's advice. Ironically,
Speaker 2: people with chemophilia that did not contract HIV during the
Speaker 2: nineteen eighties were mostly people who couldn't afford to pay
Speaker 2: for the concentrate. The HIV AIDS crisis led to an
Speaker 2: enormous breach of trust between people with hemophilia and those
Speaker 2: they believed to be their advocates, either these large organizations
Speaker 2: or their physicians, or even to some degree, the pharmaceutical
Speaker 2: companies that were producing these factors. And it, you know,
Speaker 2: there were some good things that came out of it, right.
Speaker 2: It led to the formation of new groups and new
Speaker 2: organizations whose focus is on righting some of these wrongs,
Speaker 2: on setting standards for public health and achieving social justice
Speaker 2: and ensuring that whatever products that are available to people
Speaker 2: with hemophilia, that they're safe. But this breach of trust
Speaker 2: is still felt today, as is the sense that there
Speaker 2: needs to be constant vigilance over the safety of the
Speaker 2: blood supply, especially with things like krus Felt Yakub reaffirming
Speaker 2: that vigilance. Right. So, Aaron, this is a bit of
Speaker 2: a grim ending, but I'm wondering if you could tell
Speaker 2: me where we stand with hemophilia today and if there
Speaker 2: is any good news on the horizon.
Speaker 3: There is I can tell you that at least. So
Speaker 3: let's take a quick break and then get into it.
Speaker 3: It's not like really rosy news, but it's at least
Speaker 3: like there's a sunrise coming.
Speaker 2: Okay.
Speaker 3: So we'll first go over some overall numbers worldwide. The
Speaker 3: estimates is interesting. The estimates from the early two thousands
Speaker 3: are often thrown around, and that estimate is that around
Speaker 3: four hundred thousand people are living with hemophilia worldwide. That
Speaker 3: estimate was based on numbers mostly from the US. It
Speaker 3: didn't distinguish between severe and more moderate or mild phenotypes
Speaker 3: of disease. Okay, it was, you know, just based on
Speaker 3: one country worth of data and then extrapolated to the
Speaker 3: whole world. And a caveat with all of this numbers
Speaker 3: data is that this is only looking at males with hemophilia.
Speaker 2: That's okay, all the types of hemophilia.
Speaker 3: Yeah, and the two thousand numbers didn't distinguish all types.
Speaker 3: This is for A and B. But it didn't distinguish
Speaker 3: between moderate or severe, et cetera. So you can imagine
Speaker 3: that data it's not only but it also was like
Speaker 3: never that great to begin with. So luckily we have
Speaker 3: some newer data, and this newer data it's based on
Speaker 3: several different countries data. It also takes into account things
Speaker 3: like the variability in prevalence across different countries. It calculates
Speaker 3: the impact of things like the severity and the discrepancy
Speaker 3: between the prevalence of hemophilia at birth and then the
Speaker 3: overall prevalence in a country to try and get a
Speaker 3: better measure of the overall impact of this disease. So
Speaker 3: this more recent data suggests that for all of hemophilia
Speaker 3: A that's missing factor eight, the prevalence is about seventeen
Speaker 3: per one hundred thousand males worldwide. For hemophilia B, it's
Speaker 3: three point eight per one hundred thousand males worldwide, And
Speaker 3: of course it's not exclusively males that can be affected.
Speaker 3: But this is just the data that we have for
Speaker 3: severe phenoth types. So that's for everyone, but for severe
Speaker 3: phenotypes it's six per one hundred thousand for hemophilia A
Speaker 3: and one point one per one hundred thousand for hemophilia B. Okay,
Speaker 3: But what's really important is that those are the numbers
Speaker 3: of the overall prevalence. Those numbers are lower than the
Speaker 3: estimated hemophilia presence at birth. So they did this calculation
Speaker 3: to kind of incorporate those differences to get an estimate
Speaker 3: of not only the total number of people worldwide that
Speaker 3: are likely living with any degree of hemophilia, as well
Speaker 3: as the life expectancy disadvantage is what they called it
Speaker 3: because of this discrepancy. So overall, this paper estimated that
Speaker 3: over a million people worldwide are living with some degree
Speaker 3: of hemophilia, and over four hundred thousand, which is again
Speaker 3: that estimate from two thousand, are living with severe hemophilia.
Speaker 3: So that means very low or non existent levels of
Speaker 3: factor eight or factor nine, right, So these are way
Speaker 3: higher than previous estimates. And then they also calculated this
Speaker 3: life expectancy discrepancy, which in high income countries was over
Speaker 3: thirty percent and was much higher in lower income countries.
Speaker 3: So we still have a ways to go. Yeah, so
Speaker 3: let's talk about kind of the good news, shall we.
Speaker 2: Let's do it.
Speaker 3: So I'll just go over a few of the kind
Speaker 3: of novel developments that have happened, and then we'll look
Speaker 3: to the big question, which is can we cure this? Right?
Speaker 3: I feel like that's the big question. So just in
Speaker 3: terms of actual treatment, improvements that we've had for people
Speaker 3: currently living with hemophilia. There have been major improvements in
Speaker 3: the coagulation factors themselves, so people have developed coagulation factors
Speaker 3: that persist a lot longer in the bloodstream than just
Speaker 3: pooled coagulation factors. These are like recombinant coagulation factors, so
Speaker 3: that you don't have to give these infusions as frequently,
Speaker 3: so that's pretty major. There also is a monoclonal antibody
Speaker 3: which has been used and has been shown to be
Speaker 3: pretty effective at reducing bleeding episodes as well as severity
Speaker 3: and these. This monoclonal antibody also seems to work in
Speaker 3: people who have developed inhibitors to factor eight, which we
Speaker 3: mentioned briefly earlier, so that's pretty incredible. And this monoclonal
Speaker 3: antibody can be injected under the skin instead of into
Speaker 3: a vein, so it's easier to administer and it's only
Speaker 3: every two weeks that you have to administer it. But
Speaker 3: of course, for all of these treatments, there's still a
Speaker 3: chronic treatment. There's still major issues with cost, especially antibodies
Speaker 3: are extremely expensive and availability. These things are not widely available,
Speaker 3: especially when we talk about across the globe. So can
Speaker 3: we cure this disease? We've talked about this in a
Speaker 3: few of our genetics episodes, because the first thing that
Speaker 3: people think of when we talk about can we cure
Speaker 3: a genetic disease is gene therapysper. No, no crisper on
Speaker 3: this one, Oh man, I was sure really good guess though, no,
Speaker 3: I haven't found. I haven't found. It doesn't mean there's
Speaker 3: not people working on it, but gene therapy at least
Speaker 3: is further along in the process. We've touched on this
Speaker 3: and a few different episodes, but the basic gist of
Speaker 3: gene therapy is, like Crisper, a single dose of treatment
Speaker 3: that either alters the existing defective gene or more likely
Speaker 3: replaces the gene by adding in an effective version. And
Speaker 3: what's great about this is that it doesn't matter what
Speaker 3: you're underlying mutation is. If we can just replace that
Speaker 3: gene entirely, then now this new version of the gene
Speaker 3: can make a bunch of great factor eight or factor
Speaker 3: nine and lifelong, no more disease. I'm not going to
Speaker 3: get into the specifics of all these different trials, but
Speaker 3: there have been a number of them. I'll post a
Speaker 3: link to a kind of very recent from twenty twenty
Speaker 3: overarching analysis of how do all of these studies look
Speaker 3: so far. These studies have been done for both hemophilia
Speaker 3: A and B, and they're pretty promising so far, which
Speaker 3: is awesome.
Speaker 2: That's great.
Speaker 3: What they've done so far is used an adenovirus vector,
Speaker 3: so that's a little viral vector that expresses a functional
Speaker 3: human factor eight or factor nine gene. They've put it
Speaker 3: into people just one time, and in most cases we've
Speaker 3: seen major increases in plasma levels and reduction of bleeding episodes.
Speaker 2: That's fantastic.
Speaker 3: Yeah, it's it's really it's really exciting. And again I'll
Speaker 3: link to a couple of different papers that have more
Speaker 3: specifics on these different studies. But they are really promising
Speaker 3: and there's like more participants involved than I expected. Like
Speaker 3: these studies are farther along than a lot of other
Speaker 3: gene therapy papers I've read. These are in humans. We
Speaker 3: have good data on this, it's not just in mice,
Speaker 3: right right, right, yeah, yeah, So that's the good news
Speaker 3: on the horizon. When is it going to make it
Speaker 3: all the way across the globe for those one million people?
Speaker 3: I don't know, well, that's hemophilia.
Speaker 2: And that's temophilia. This is a this is a big one.
Speaker 3: It was, but I really enjoyed it.
Speaker 2: I enjoyed it too. I learned a lot and there's
Speaker 2: a lot of themes to fit in here. Yeah, good takeaways. Cool,
Speaker 2: should we do sources we should? Okay, I'm just going
Speaker 2: to call out a couple of books. One is one
Speaker 2: I already mentioned, Nicholas and l Alexandra by Robert Massey,
Speaker 2: a really fascinating read on the history of the last
Speaker 2: Russian Imperial family. And then the other one that had
Speaker 2: the most incredible amount of hemophilia history and whatever information
Speaker 2: is called The Bleeding Disease by Stephen Pemberton.
Speaker 3: I have actually not a ton of sources for this on.
Speaker 3: I had some just really nice comprehensive ones. So there's
Speaker 3: a nineteen ninety four paper in New England Journal of
Speaker 3: Medicine by Hoyer just called Hemophilia A. That's a nice
Speaker 3: review mostly of hemophilia A, but they touch on the
Speaker 3: other hemophilias as well. Also, the paper that looked at
Speaker 3: the global prevalence of hemophilia was by Eurio at All
Speaker 3: from twenty nineteen in the Annals of internal medicine, and
Speaker 3: then the one about therapy is by Minucci at All
Speaker 3: twenty twenty in Hematologica. There's a few others. We'll post
Speaker 3: the sources for this episode and all of our episodes
Speaker 3: on our website. This podcast will kill you dot com.
Speaker 2: That is correct. Thank you so much again to the
Speaker 2: provider of our first hand account for taking the time
Speaker 2: to chat with us and share your story.
Speaker 3: Yeah, thank you. Thank you also to Bloodmobile for providing
Speaker 3: the music for this episode and all of our episodes.
Speaker 2: And thank you to the Exactly Right Network, of whom
Speaker 2: we are a very prid member.
Speaker 3: And thank you to you listeners.
Speaker 2: We love you.
Speaker 3: I hope you guys liked this episode. We do love you.
Speaker 3: A special shout out to our patrons. Thank you, thank you.
Speaker 2: We love you. Okay, well, I guess until next time.
Speaker 5: Wash your hands you feel the animals.
Speaker 2: U um um