Ep 79 Hemophilia: A Hemorrhagic Disposition

I always knew that my dad had hemophilia. I can specifically remember we had a whole shelf in our refrigerator full of these little white boxes of factor nine, which as a kid, I didn't really know what they were, but I knew, like, pretty frequently my dad would have to take one of those boxes into his room and he'd close the door and we'd have to leave him alone for an hour, and as I learned as I got a little older, he would be transfusing himself with

factor nine. He was a wonderful dad, but you know, because of a long history of bleeding into his joints, he couldn't interact with us the same way maybe other dads would. He had a lot of joint pain and it was visible in his hands and his feet, and he would try his best, but I think I drove him crazy wanting to be carried constantly, which he could not do, and we just always wanted to, you know, play like little kids do, and he'd have to try

his best and then step back from that. I'm sure we probably contributed to him needing to transfuse more than otherwise he would have but that's okay. He never minded, He never complained at all. So when I reached around puberty, maybe I was told earlier, but I definitely distinctly remember being told, you know, hemophilia is genetic, and that they found out when I was born that I was a carrier, but they would need to find out if I was

a symptomatic carrier. So in my probaly between ten and twelve, went to the hospital, got some tests done and found out, sure enough, I am a carrier, and not only that, but a symptomatic carrier. Nowadays, they actually just consider women who carry that gena dar symptomatic to just have chemophilia. They don't call symptomatic carriers anymore. So, like my dad and actually both of his brothers, I have hemophilia B,

a factor nine deficiency. Unlike them, mine is mild and doesn't affect my life day to day, since two out of the three of them are no longer alive to speak to their own stories and tell you a little about them. So, my dad and his older brother both had very severe chemophilia B. They produced zero factor nine on their own, and they were born in the nineteen fifties,

which was before pretty much any good treatment existed. All three brothers, actually, my grandmother used to tell me, they refused to cooperate with all the restrictions on their behavior, and at the time, the lifespan for them was expected to only be into their twenties, so my grandmother tried as hard as she could to keep three young boys

well contained, and they didn't cooperate at all. My dad even at one point took me down the road from his old house to show me the field where they would all go play football and subsequently all need to be driven to the hospital to get blood transfusions. So my grandmother said their childhood was full of at least one trip to the hospital every week, and it was so frequent that their pediatrician would actually pick them up

at her house and bring them there himself. I can't imagine having a childhood like that, and I also suspect it probably contributed to a lot of the symptoms my dad had just from just constant bleeding. But I also can't imagine living a life as restricted as kids with humohilia really needed to Back then, when I was actually soon after I found out that I was also a

carrier and symptomatic with humophilia. My uncle became symptomatic with his HIV, had SYRUH converted to AIDS, and I never knew growing up that he had HIV, and I never knew that my dad had hepatitis C. But when he got really sick, my dad found it important to sit us down and tell both me and my sister that that they both developed HIV, and then my dad HEPSI and my uncle as well HEPSI as a result of blood transfusions and blood products because back when they were

young and getting them, they didn't know that they contained all these viruses. And they told me then that about half of all people with hemophilia back then would go on to get these diseases, and never really gave me a number on how many of them died, but I understood them that it was pretty grave. So when I was fourteen, my uncle passed away from implications from HIV and AIDS that again he contracted as a result of

treatment for his hemophilia. When I was in my early twenties, my dad also passed away from complications of hepatitis C,

again from requiring blood products for hemophilia. I remember for my dad it was really profound he actually, up until the point that he got really critical with his hepsia, had said that it was almost like a silver lining of hemophilia to get hepatitis c because a liver transplant actually would have functionally cured his hemophilia, and he felt that life post transplant would have been a better quality than that of living with hemophilia, even with home transfusions

and all the other treatment options, which is really devastating to think about, especially knowing how positively he viewed life and how little he complained. So for me personally, like I said, day to day, my quality of life isn't impacted, although I do have other medical issues and hemophilia always complicates those. So when I go to a doctor and we're talking about treatment options for other things, my bleeding and clouding status is always at the forefront of my

doctor's minds. Whether I need to be hospitalized inpatient for something that other people would go home from the same day, whether I need to be infused with factor before during after the next day, whether I need to take something like amacar for a mild procedure, and even down to the reason I had had to go back when I hit puberty for periods which are heavy and really unpleasant, which everybody deals with, I'm sure, but for someone with

heem affiliates particular gularly burdensome. And I always worry if I get into a car accident or some sort of other trauma, if I don't go to a hospital that has my records or my husband's not with me to tell somebody when I'm bleeding. Will they give me normal blood or red blood cells, which will only thin out my factor levels even more, dilute them even more, or will I be okay? But mostly I'm grateful that I

was born when I was in the eighties. I'm grateful that one of my uncles is still alive, that he was born later than the other two and has suffered less because things like cryo precipitate were already known about in his early childhood. And other than that, I think that hemophilia is It's not something we hear about regularly, but it's it's a fascinating look at a disease that can just ravage an entire family line, one that can

have devastating impacts if it's not diagnosed early. Living with humophilia now is so much easier than it used to be. But I think that even though the treatment options have improved dramatically, we can look back at the very recent history of this disease and see that it's really important to evaluate, you know, looking for treatment options, but also evaluating the safety of them, because the impacts that they can have on the people that we're treating can be really devastating.

those are the main symptoms. So this episode's fun because we're gonna go over in very general terms some really basic human biology, and that is the clotting cascade.

blood is very important in our bodies. It's how we carry nutrients and oxygen to all of our tissues, and it's how our cells offload carbon dioxide and waste products to be carried to our lungs, our liver, et cetera. And in our human bodies, blood is inside of blood vessels, and that's where it's supposed to remain. If the walls of our blood vessels get broken, we bleed. We all know this, right. If you get a cut on your skin, you break the walls of tiny little blood vessels and

you bleed. And because bleeding outside of our vessels is bad, our body has mechanisms to stop this from bleeding. Everything from tiny scratches up to larger breaks in the vessels. So very broadly, when a blood vessel wall gets disrupted, there's kind of a series of three steps that happen to fix it. First, you plug the hole like stick your finger in it kind of plug, just so that

you don't lose any more blood. Second, you a fix that plug into place with something a little bit more sturdy so it doesn't come unplugged in like the near term. And then finally you have to prepare that whole area, if possible, so you don't break it in the same spot.

take their sweet time getting over there. But that duct tape is strong, so it'll hold it until it can be fixed properly. Easy, easy, Right, That's what we do in our human pipes. When a blood vessel wall is disrupted, the first thing that happens is our platelets, which I feel like we've talked about a bit on this podcast. Platelets are just these little cells, kind of little chunks of cells that are in our bloodstream and they're super sticky, so they float past that hole in the blood vessel

wall and they stick themselves. They turn on their stickiness and they stick themselves to just plug that hole. First thing, gum in the hole. That's your platelets. But gum that you just threw down in a panic doesn't hold that flow forever. And obviously in our bodies, we can't just like find duct tape, right because if you had a bunch of duct tape just floating around your bodies, you'd be clogging up your pipes because duct tape is really sticky.

So we in our bodies have to actually make the duct tape from scratch, and that is where the coagulation cascade comes in.

to be activated before it can do its job. And the series of events that have to take place, it's kind of maybe I'm getting too excited about it, but it is the coagulation cascade. And if any listeners have seen this drawn out on paper aerin, you probably have way long time ago.

aka duct tape. I'm not going to go over the specific series of events because it's not really that important for this, but you can imagine that if number one is fibrin, which it is, and number twelve is like the top of the chain, you kind of are moving down to try and make fibrin. So anything that's missing or doesn't work correctly between numbers two and eleven means that you're going to interrupt that whole process and not be able to make fibrine.

certain factors in this clotting cascade. Okay, so, like you mentioned, Aaron early on. There's a number of different types of hemophilia. They all have slightly different clinical pictures, but overall, if you think of them as not being able to clot blood efficiently, then they're all pretty similar. So hemophilia A, which is the most common, is when you have a problem in the production of factor eight. That's one very important factor in the clotting cascade. Hemophilia B is when

there's a problem with the production of factor nine. And those two are the kind of main diseases that we call hemophilia, And they actually look very similar because factor nine in factor eight work together in the clotting cascade. So those two diseases are like very very similar. Clinically they look about the same. You have to do like factor analysis how much factor eight versus how much factor nine do you have in your blood to know which one you have?

you google hemophilia, that's what you get. So these are both genetic disorders, and both hemphilia A and hemophilia B are X linked recessive disorders. I don't think we've covered any of these, have.

of hemophilia to one degree or another. If you have two copies of the X chromosome, then you most likely won't have any symptoms of disease, but you will be what's called a carrier because you have that mutated gene and can then pass it on to offspring. And this makes sense because I said that this was all a cascade, right, You only need a very little bit of factor eight or factor nine to be able to effectively activate this cascade.

So you have to have a reduction of like eighty to ninety five percent of typical plasma levels of factor eight in your blood to actually have symptoms of hemophilia. So if you have even just one normal gene that makes a little bit of factor eight, then you're not gonna have symptoms of hemophilia.

where they didn't have any surgeries? Maybe not. So there's there is a huge spectrum and then even between eighty percent, Like if you have an eighty percent reduction, so you have twenty percent of factor eight versus someone who has zero factor eight. There's a huge spectrum of disease severity within that as well.

So yeah, it's a it's a very big spectrum. But if we focus in on the more severe hemophilia, which I think is what we think of classically as hemophilia, then we can talk about the symptoms and know that if you have less severe disease, you would have less severe symptoms. So the symptoms, unsurprisingly are bleeding. This bleeding can be uncontrolled, it can be potentially life threatening. One of the hallmarks though, of where you get this bleeding

is bleeding specifically into joint spaces. This is something called hemarthrosis. You can also get bleeding into muscle spaces. You can get potentially life threatening bleeding after a trauma or surgery.

But one thing that is interesting about hemophilia A and B, unlike some other coagulopathies that affect other parts of the cascade or affect maybe platelet function, like that gum, you generally don't have severe or prolonged bleeding after minor cuts and scrape Okay, okay, why yeah, because the very first thing that happens when blood vessels are damaged is we put gum on them.

also very inflammatory. So even as the bleeding eventually slows and stops, because you have like the other arm of that coagulation cascades, like eventually you'll stop the bleeding, but you then trigger intense inflammation in that joint space because of the blood that's accumulated, which can then lead to sinovitis, which is inflammation of the connective tissue in the joints. That is very painful in itself, but it also can increase the likelihood of additional bleeding into the joint space

because that area is inflamed. So it's this vicious cycle. Yeah yeah, and this can and often does lead to permanent disability because of these effects on the joints, So that's bad number one. Yeah, a similar process can happen

in muscles. However, muscles, on the one hand, have more space in them, but large hemorrhages into muscles have the potential to compress other vital structures, so that can lead to things like nerve damage or other blood vessel obstruction, which can lead to like compartment syndrome, which is where you block off the blood flow to areas of your body because of that swollen muscle, and that's an emergency.

And then of course hemophilia can also lead to death directly because of these hemorrhages, whether it's in the gut or the liver, but especially in the brain. So intracranial bleeds bleeds from blood vessels in the brain. I think, in before there was any treatment available, accounted for about twenty five percent of deaths in people with hemophilia.

sufficiently duct tape our leaky pipes. Right, All of our blood vessels probably break and bleed at one point or another in our lives, Like you bonk your knee gently on a table, or you trip and fall down a flight of stairs, or you're a kid and you just ran and jumped off of a table just for fun. Right, Without the ability to quickly duct tape and patch those leaks, you get this uncontrolled bleeding. That's what hemophilia is, right, And there's no opportunity for the actual like healing and

repair exactly right. But it is important to know that whether you're talking about heemophilia A or hemophilia B or some other coagulapathy. There's a very wide range of severity because, like I said already, even though this is a genetic disorder, it's not one single mutation, So there is a really

wide range. And some people might not have any of these symptoms, but might, you know, as an adult bleed a lot after a tooth extraction and then later find out, oh I have low levels of factor eight or whatever. So yeah, that's that's hemophilia.

so it requires a lot of IVY infusions. Also, anytime that you introduce something into the body like repeatedly, that's especially that's a blood factor, then make antibodies against it, and so you can end up with what are called inhibitors against these factors. So then the treatment becomes less effective.

It can of course affect other animals like dogs, which has actually been helpful in a number of ways since there are then appropriate animal models that you can use to study some of these different forms of humophilia. But not only has it probably always been around in humans, humans have also noticed it for a very long time.

The earliest known references to bleeding disorders come from the Talmud from the second century CE, where it was written that male siblings are exempted from circumcision in cases where other male siblings in that family have died from the ritual yep, and there are other things like that in terms of like regulations or advisements, and throughout the medieval period there are additional mentions or descriptions of fatal bleeding disorders,

but the real history of this disease doesn't begin really until the eighteen hundreds, and even then it's I would describe it as fairly light until the twentieth century, which for me, or at least like the late eighteen hundreds, which for me, totally goes against what I had, you know, had of this perception of hemophilia before doing this episode.

a number of reasons. One is that it noted the familial nature of the disease and the fact that males tended to be affected. Quote, it is a surprising circumstance that the males only are subject to the strange affliction, and that all of them are not liable to it. Although the females are exempt, they are still capable of transmitting it to their male children.

were rarely useful. Most of them were just like a strong, gross cocktail full of mysterious ingredients and like beef liver or something, and bleeding was a very common treatment still.

possible treatments which there weren't any. Right, And while the disease remained hot for a while in the US, where it mostly picked up traction was in Germany, where the disease had become fairly well known during the early decades

of the eighteen hundreds. And Germany was also where formal metic training and this high prevalence of hospitals is allowed for more data collection and also central places with a high volume of people going through So you just have more frequency of people with hemophilia.

improvement on treatment or management during this time. There was a physician in Germany, Ludwig Grandidier, I don't know how you say it, who helped to spread a uniform understanding of this disease throughout Europe, and he also compiled stats on hemophilia and life expectancies which were extremely grim. So, just to put a number to it, more than fifty percent of the people with hemophilia that he documented ended up dying before they were eight years old, Oh my god.

And of those that did survive past eight, only twelve percent made it past their twenty first birthday.

when stats began to be used in medicine. And also if you think back to our Huntington's Disease episode, it's also when genetics began to be used to declare who should or shouldn't be reproducing, aka eugenics. Eugenics Aaron, do you remember when you first learned about hemophilia, Like in what context?

explicit suggestion that quote bleeders should be prohibited from reproducing. Often, though, eugenesists argued that men with hemophilia should be allowed to marry because their sons would not be affected, but that the daughters should then be prohibiting from reproducing. Just infuriating, of course, and this suggestion taps into a couple of the themes of this disease. One is this historically gendered perception.

For the longest time, it was thought that only males could have hemophilia, and being male was real requirement for

a diagnosis. Women who presented with a bleeding disorder were often diagnosed with like parahemophilia or something to that effect, not real hemophilia, but something that looks a lot like it, and a lot of the language that was used to describe women with a hemophilia allele was pretty accusatory even once eugenics died down, and the boys with the disease were often portrayed as not having or being able to have masculine traditionally masculine traits, am using masculine quotes, you know,

being able to run around and play rough and climb trees and shoot guns or whatever it is that was, you know, masculine, and this gendered perception of hemophilia, where hemophilia in a way was like making you less masculine. And then the ideal, the quest for normality meant being able to, you know, ride on a bike and I don't know, do wheelies. Yeah, to be a man. That's the only thing I could think of about bike riding.

it led to a substantial amount of stigma surrounding hemophilia. Yeah, and while many eugenicists or geneticists in Europe and North America felt free to add to the stigma as much as they wanted by making recommendations on who should or shouldn't be allowed to reproduce, many physicians in England had

to be a bit more restrained. And that's yeah, you know why because the pedigree, right, that's because of Queen Victoria, who unknowingly passed along the hemophilia alile she was actually in denial about it to three of her children, her son Prince Leopold, and two daughters, Alice and Beatrice. In this story, this passing of the hemophilia aliele to several of her children and then several of her grandchildren led to hemophilia getting the nickname. Of course, the royal disease.

So rather than taking this eugenic stance, the prevalence of the disease in the royal family and the descendants led British physicians to instead focus more on treatment and management. And it also in a way, just like overall, increased this interest in the disease.

because it is such a fascinating chapter of history. But I'm just going to go over this story briefly, and if you want more info, I highly highly recommend the book Nicholas and Alexandra by Robert Massey, who, by the way, was partially inspired to write it because his son, just like the last heir of the Russian throne, Alexei Romanov, had hemophilia. Okay, so Nicholas the second and Alexandra were

the last Emperor Empress of Russia. Alexandra was the granddaughter of Queen Victoria, and she had inherited a copy of the Hymophilia Alile, which she passed down to her son, Alexei, who was the baby of five children and the only boy, and so he was the heir apparent to the Russian throne.

And Nicholas and Alexandra became aware of their son's disease pretty early in his life, which, as you mentioned, is often the case, and they went through great efforts to protect their son from any injury that could prove deadly and also to conceal his disease to the public, and he figuring in some pretty horrific bleeds, as she has in a lot of her letters, Alexandra, they still exist and it's just like heartbreaking, the amount of pain I

can't imagine. And around this time, in the early nineteen hundreds, treatments for the disease were still nonexistent and doctors had actually started to use aspirin often, which only made the bleeds worse. And Alexandra, who of course cared deeply about her son's safety and also as the Empress, knew that part of her value was wrapped up in producing an

air to the throne and getting him to adulthood. She did everything in her power to keep Alexi alive, including reaching out to a faith healer by the name of Grigory Resputin Resputin Rasputin, who had promised to keep Alexi safe. Alexandra and Nicholas, they were desperate for their sol well being and that made them utterly loyal to Resputant, afraid of upsetting him and losing his healing powers, which were I mean yeah, and Resputant completely took advantage of this.

He demanded that they appoint ministers of his choosing, kick out the ones that weren't his, that weren't a fan of his. He wanted to be informed of any army movements during World War One, and basically he just wanted to have complete freedom to do whatever he wanted and

not lose any power. And their reliance on Resputant, their utter loyalty blind loyalty to him led to ultimately a lot of discontent among the Russian people, and it led to the February Revolution of nineteen seventeen, when the monarchy was abolished and the royal family, after a period of exile, was executed, including Alexi and Anastasia. Despite what the animated movie might have led you.

history might have played out differently. And I find all that super interesting, and again read the book Nicholas and Alexandra for more on that. It's great, But as much as I would love to discuss hypothetical alternative histories, instead going to move back to solid to see how things

changed for people with hemophilia in the twentieth century. Eventually, early on, the eugenicists were silenced, in part because eugenics was starting to fall out of favor, and also because they realized that their plans for large scale sterilization weren't practical For hemophilia, they still performed plenty of sterilizations otherwise because the rate of new mutations was so high, and so attention then turned more towards understanding the disease and

the hopes that it would shed some light on possible treatments. So although the clinical definition of hemophilia was well recognized by the early nineteen hundreds, the path of physiological nature was less certain. Like all doctors knew was that bleeding was difficult to stop. What step They didn't even have a cascade yet, like they had no idea. Many doctors had hypothesized that it was actually due to heart malformation or a degenerative blood vessels, or maybe even a spleen abnormality.

And this was like in the early days, it was just a constitutional deficiency, like, oh, you have a weak constitution, like you're in a Jane Austin novel or something.

in the mates from the past episodes. So this guy, though, observed that the average clotting time for a child with hemophilia was two to three times longer than it took for his own blood to clot And this was a big deal because not only did it open the door a bit for a diagnosis, even though clotting times was a pretty crude method and not the most reliable, but it also showed that the disease was a clotting disorder, right,

it wasn't a heart malformation or whatever else. And that also meant that if you could treat the clotting, you could potentially treat the disease, possibly by adding substances that

helped clot or more practically, through blood transfusions. But if you remember from our Hepatitis C episode where I talked a lot about the history of blood transfusions, they were by no means routine or remotely safe in the early nineteen hundreds, not at all, and there was still a lot of lingering controversy from the previous sent or centuries really that had made them illegal actually in many places,

which didn't mean they weren't performed though. If you remember, in eighteen forty, there was a transfusion performed on an eleven year old boy with hemophilia who was on death's door before receiving the blood. Somehow the transfusion worked and the boy lived, but it seemed to be an isolated attempt for at least the next seventy or so years,

at least when it came to hemophilia. Starting in the early nineteen hundreds, hematology really began to grow as a field, and this then led to a resurgence in transfusion experiments. One of these was performed by surgeon Beth Vincent on a patient who had hemophilia, and this was in nineteen sixteen. I believe. Prior to the transfusion, the donor's clotting time was seven minutes and the recipient's one hundred and fifty minutes.

that drove hematology and transfusions was improvements in sterilization. Transfusions and pre germ theory. Days often failed just due to dirty needles, right. Number three. The discovery of blood types also really kind of helped shed some light on why transfusions failed or were successful, although that was really more than nineteen twenties and thirties and number for the addition of anticoagulants like sodium citrate or sodium phosphate. These really

helped increase the life of donated blood. So it was sort of this step wise like, okay, it's just a little more info here, a little more info here, refining and you know, retooling until we have like a routine procedure. And while hemophilia was not a driving force or the reason necessarily for these improvements in transfusion technology, it would

greatly benefit from them. And I also want to point out that many people with hemophilia played hugely important roles in some of these developments, both in terms of transfusion science, but also in terms of understanding the you know, nuanced disease, that is, all of these different hemophilias or different types of hemophilia, because without their involvement and their without their willingness to provide the blood samples or their time or

their bodies for the study of different treatsments, it wouldn't have been possible to track down exactly what plotting factor was responsible for which disorder, and which treatments were effective, how much plasma to give and how often to give it, etc. By the mid twentieth century, the concept of hemophilia had undergone a dramatic change, due in large part to improvements

in transfusions. At the beginning of the twentieth century, like I said, transfusions were still a rarity, and then World War Ones showcased the need for a reliable blood supply and better ways of getting it into someone. The years that followed that war improved upon that, and then transfusions really came into their own and became routine during World War II, which is also when blood banks were established

and the concept of blood donation became widespread. Alongside all of these wider developments for the fields of hematology and transfusion science came this huge revolution inphilia. At the start of the century, it was viewed as an acute disease, and in practice it was. I mean, you heard the numbers that I cited from that German physician, right, it was hugely deadly. There were no effective treatments, and this

life expectancy was dismal. But by the nineteen fifties, the availability of transfusions and growth in knowledge about the disease had turned hemophilia into a manageable chronic disease, a disease that you live with for years and years and years. The development of essays in the nineteen fifties for identification of clotting factors led to this much more nuanced understanding

of bleeding disorders overall. And this also drew into question the historical assumption that there had to be a family history of bleeding, or that the person had to be male, had to have just one X chromosome.

to put the need for blood in perspective. I'm gonna cite one very widely reported case, and it's definitely an outlier, but I do think it is sort of eye opening. So there's a thirty one year old person with hemophilia who received a record two hundred and thirty two pints of whole blood and one hundred and sixty eight pints of plasma while bleeding continuously for four hundred and twenty two hours. Oh my, yeah, it's a lot of blood.

blood and or plasma. And these stories were powerful in that they garnered a lot of support for blood drives, but they also kind of drew on the old stigma of someone with hemophilia being sickly and vulnerable, always reliant on the generosity of others. And it's kind of like this paradox where this increased visibility and having to showcase the challenges of living with hemophilia was the only way to ensure a quote normal life and not having to live with the challenges of humophilia.

and many of these efforts paid off. The nineteen sixties saw the continued transformation of hemophilia into a manageable disease, and that was especially helped along by technological advancements like plasma paresis, which allowed people to donate plasma more frequently and cryo precipitate, which allowed for the concentration of particular clotting factors and was much more potent than fresh plasma

in stopping bleeds. And while cryo had some pretty big advantages over plasma, like increased autonomy with home administration and quicker access, it still had some drawbacks. Many physicians didn't allow their patients to administrate at home, and if you were experiencing a bleed, you still had to wait to have it fall and endure that horrific pain as you waited,

and there were still issues with shortages. The real dream was in clotting factor concentrates, a dream that would be realized in the late nineteen sixties when factor eight concentrate first became commercially available, sourced from for profit plasma centers, which had less of a supply issue than those that

were strictly volunteer. The development of factor eight and other clotting factors had vastly improved the quality of life and the health status of many people with hemophilia, and the leading voices in these hemophilia advocacy groups were increasingly those of the people with hemophilia themselves rather than their parents, as they were living to be older and older, and

one thing became very clear. While cryo and clotting factors were incredibly effective at managing hemophilia, they were also incredibly expensive. And this wasn't a one time expense, right, This was a chronic disease. This was years of weekly or monthly costs, and the conversation then turned towards medical care as a right rather than a commodity, as clotting factor as a rite rather than a commodity, and hemophilia advocacy groups in

the US. And this, most of this history, I forgot to say, is focused on the US, because that's where the book that I read and got a lot of this is largely from. And the history is already enormous as it is. But I do want to note that many other countries in Europe, the clouding factors were paid for by the state already, no question, right, They didn't have.

more health coverage, when in reality it absolutely wasn't. It was cut down in so many areas that created this massive competition both among different government agencies and also across different disease support groups to determine which disease was worthy of support, right Like, each group had to advocate for themselves like no, I'm worthy, No I'm more worthy, And in this case, the hemophilia advocacy groups did have a

bit of a leg up. First of all, they had been working in the public eye for almost two decades by that point, raising awareness about the disease and then pushing for these blood donations. And secondly, with the development of clotting factors and other plasma treatments, they had established themselves as consumers, right because they still weren't having these things subsidized, and that status as consumers gave them more, say,

especially with Nixon gross I know. And thirdly was public perception. People with humophilia were often portrayed a as quote socially creditable, as in, you know, with access to treatment, they could be productive members of society and live quote normal lives, and so they deserved more funding than those viewed as hopeless causes, right.

And the author of this book that I read argues that this, you know, socially creditable status was a big factor in getting a comprehensive care bill successfully passed in nineteen seventy five that subsidized programs for people with hemophilia in the US. So by the mid to late nineteen seventies, things were looking up right. Doctors were now advocating for at home transfusions or concentrate injections, which had greatly increased

the autonomy of people with hemophilia. There were improvements in treatments that were always happening, and for many people with hemophilia, the state sponsored financial support was helping to manage their healthcare.

In this numisicististemonia case, this was part of a larger alarming trend of outbreaks of these opportunistic pathogens killing people

who had been healthy. Just months before the report of this man with hemophilia dying of pneumsistas pneumonia set off alarm bells at the CDC and made the hematologist there think that whatever was causing this outbreak of what immune syndrome, it might be bloodborn and additional cases of this emerging immune syndrome and other people with hemophilia fur their support of the blood born pathogen hypothesis, and it suggested to doctors,

especially doctors of people with haemophilia, that there were going to be many more on the horizon. Despite this, the risk to people receiving blood transfusions, not just people with hemophilia,

but anyone who would receive a blood transfusion. It was frequently downplayed in the early months of the AIDS crisis, or even in the early year and in part because it was simply not known how long the course of disease was, how long the incubation time was, and also because the hemophilia community had been fighting for so long for these life saving treatments and for access reliable access

to them. And it also must be said that part of the reason it was downplayed was probably because of the commercial interests of these blood and plasma banks or

pharmaceutical companies making these blood derived products. Yeah, definitely, it is horrifying in retrospect to read this statement, for example from the National Hemophilia Foundation in nineteen eighty two quote, the risk of contracting this immunis depressive agent is minimal and CDC is not recommending any change in blood product use. At this time, the blood borne hypothesis started out controversial, and many organizations demanded more solid studies before any policy

changes were made regarding the blood supply. Eventually, additional cases in nineteen eighty two showed that the pathogen could be transmitted through blood, but the causative agent was still unknown at this time, so there was no way to screen

the blood against it. Alternatives to screening were proposed, such as barring quote high risk individuals from donating or screening for hepatitis B as a surrogate, since there was a high correlation between BEE prevalence and this unknown immune syndrome.

And the controversy surrounding these decisions is part of a much larger conversation, and it's one that we touched on a bit in our HIV AIDS episode from our first season, and it's been cover in depth and many books and articles elsewhere where they would do a much better job than I would ever do, so I'm not going to

go into it here. But the result of many of these decisions, the delay in action and policy, the type of decision that was made, the denial that many blood bank organizations and plasma companies expressed that their blood supply could be dangerous. The result of all of this was that many, many people with hemophilia became infected with HIV, even after blood bank testing for the virus began in nineteen eighty five.

The term canary in the coal mine has often been used, and that does imply a bit of like intent in some ways, and I'm not sure if it's like the most appropriate term, but it is true that there have been, you know, even back in the nineteen seventies, extremely high rates of hepatitis B, like over fifty percent in people with hemophilia, and also hepatitis C. Those are what they had called at the time, non A non be hepatitis.

Those had been observed at least starting in the seventies, But what was often the case was that these infections they were often viewed by physicians as sort of the lesser of two evils, and some did not even disclose

the infection to their patients. Oh goodness, right, And so then when there was the switch to clotting factor concentrates, especially using pulled human plasma, So like one lot of this of these clotting factor concentrates could have plasma from ten thy to twenty thousand individuals, and so hepatitis B in C cases soared. At that point, one person infected with one of those pathogens who had donated plasma, that

could lead to that entire lot testing positive. So in the context of this pooled clotting factor concentrates and sort of the unwillingness of some doctor to sound the alarm or the inaction whatever, it might not be surprising, but it is still horrifying to learn that by nineteen ninety four, more than twenty five percent of people with hemophilia in the US had died of causes related to AIDS, and an overwhelming majority of people with hemophilia had contracted the virus.

Of the eight thousand people with severe heemophilia in the US in the early nineteen eighties, nearly ninety percent would acquire HIV, and their partners often became infected as well, with many dying also. The AIDS crisis once again put people with hemophilia in the public eye. One of the most famous was Ryan White, who I mentioned before. This was a boy a young boy from Cocomo, Indiana, who had been kicked out of school by parents who were

afraid for their kids after he tested positive for HIV. Ryan, like many other people with chemophilia, he went on talk shows to raise awareness about humophilia and HIV and also was attempting to reduce some of the stigmatization of HIV and AIDS. Unfortunately, Ryan White died in nineteen ninety and much of the stigma both towards people with hemophilia, who were viewed as quote innocent victims, as well as other people with HIV. This stigma persisted and continues to persist.

Of course, the spread of HIV changed so much of the landscape for people with hemophilia, and not just in the extremely high prevalence of infection. Many doctors didn't properly inform their patients about the risks of concentrates from large pools, and many people didn't listen to their doctor's advice. Ironically, people with chemophilia that did not contract HIV during the nineteen eighties were mostly people who couldn't afford to pay

for the concentrate. The HIV AIDS crisis led to an enormous breach of trust between people with hemophilia and those they believed to be their advocates, either these large organizations or their physicians, or even to some degree, the pharmaceutical companies that were producing these factors. And it, you know, there were some good things that came out of it, right.

It led to the formation of new groups and new organizations whose focus is on righting some of these wrongs, on setting standards for public health and achieving social justice and ensuring that whatever products that are available to people with hemophilia, that they're safe. But this breach of trust is still felt today, as is the sense that there needs to be constant vigilance over the safety of the blood supply, especially with things like krus Felt Yakub reaffirming

that vigilance. Right. So, Aaron, this is a bit of a grim ending, but I'm wondering if you could tell me where we stand with hemophilia today and if there is any good news on the horizon.

whole world. And a caveat with all of this numbers data is that this is only looking at males with hemophilia.

like the variability in prevalence across different countries. It calculates the impact of things like the severity and the discrepancy between the prevalence of hemophilia at birth and then the overall prevalence in a country to try and get a better measure of the overall impact of this disease. So this more recent data suggests that for all of hemophilia A that's missing factor eight, the prevalence is about seventeen

per one hundred thousand males worldwide. For hemophilia B, it's three point eight per one hundred thousand males worldwide, And of course it's not exclusively males that can be affected. But this is just the data that we have for severe phenoth types. So that's for everyone, but for severe phenotypes it's six per one hundred thousand for hemophilia A and one point one per one hundred thousand for hemophilia B. Okay, But what's really important is that those are the numbers

of the overall prevalence. Those numbers are lower than the estimated hemophilia presence at birth. So they did this calculation to kind of incorporate those differences to get an estimate of not only the total number of people worldwide that are likely living with any degree of hemophilia, as well as the life expectancy disadvantage is what they called it

because of this discrepancy. So overall, this paper estimated that over a million people worldwide are living with some degree of hemophilia, and over four hundred thousand, which is again that estimate from two thousand, are living with severe hemophilia. So that means very low or non existent levels of factor eight or factor nine, right, So these are way

higher than previous estimates. And then they also calculated this life expectancy discrepancy, which in high income countries was over thirty percent and was much higher in lower income countries. So we still have a ways to go. Yeah, so let's talk about kind of the good news, shall we.

pooled coagulation factors. These are like recombinant coagulation factors, so that you don't have to give these infusions as frequently, so that's pretty major. There also is a monoclonal antibody which has been used and has been shown to be pretty effective at reducing bleeding episodes as well as severity and these. This monoclonal antibody also seems to work in people who have developed inhibitors to factor eight, which we

mentioned briefly earlier, so that's pretty incredible. And this monoclonal antibody can be injected under the skin instead of into a vein, so it's easier to administer and it's only every two weeks that you have to administer it. But of course, for all of these treatments, there's still a chronic treatment. There's still major issues with cost, especially antibodies are extremely expensive and availability. These things are not widely available,

especially when we talk about across the globe. So can we cure this disease? We've talked about this in a few of our genetics episodes, because the first thing that people think of when we talk about can we cure a genetic disease is gene therapysper. No, no crisper on this one, Oh man, I was sure really good guess though, no, I haven't found. I haven't found. It doesn't mean there's not people working on it, but gene therapy at least

is further along in the process. We've touched on this and a few different episodes, but the basic gist of gene therapy is, like Crisper, a single dose of treatment that either alters the existing defective gene or more likely replaces the gene by adding in an effective version. And what's great about this is that it doesn't matter what you're underlying mutation is. If we can just replace that gene entirely, then now this new version of the gene can make a bunch of great factor eight or factor

nine and lifelong, no more disease. I'm not going to get into the specifics of all these different trials, but there have been a number of them. I'll post a link to a kind of very recent from twenty twenty overarching analysis of how do all of these studies look so far. These studies have been done for both hemophilia A and B, and they're pretty promising so far, which is awesome.

on the horizon. When is it going to make it all the way across the globe for those one million people? I don't know, well, that's hemophilia.

Russian Imperial family. And then the other one that had the most incredible amount of hemophilia history and whatever information is called The Bleeding Disease by Stephen Pemberton.

twenty twenty in Hematologica. There's a few others. We'll post the sources for this episode and all of our episodes on our website. This podcast will kill you dot com.