Monday 12 October 2015

Bleeders

One of the miracles of physiological function is that we don't exsanguinate ourselves when we have a finger-mishap while chopping onions. We cry "Oh Bugger", stick the digit in our mouths, hop about a bit and almost before we've got a sticking plaster ready, the bleeding has stopped. Evolution has encountered similar damage before and caused the development of a series of biochemical events that tangle up the disappearing red blood cells in a web of protein and cell fragments called platelets to staunch the flow. It works but b'god it's not as simple as slapping on a plaster and uttering an imprecation. Like yer foot bone's connected to yer ankle-bone etc.etc., the damage is detected and then requires a cascade of at least a dozen molecular events, each controlled by a protein. There are so many of them that science gave up giving them informative names and just numbers them: Factor I to Factor XII.
Damage -> FXII -> FXI -> FIX -> FVIII -> FX -> FII -> FI -> CLOT!
We only have 23,000 protein coding genes to do everything, so it's interest that 1/1000 of them do this simple but vital task.  Actually, you should reflect that the wall of a small blood vessel is only one cell thick and it is micro-repairs at this level that are the day-job of clotting factors rather than dramatic accidents with hatchets and saws. A bruise for most of us is the slowly discolouring evidence that a sub-cutaneous bleed has been repaired. Hemophiliacs dream wistfully about getting a bruise, because they don't - they just bleed and bleed and it hurts. Hemophiliacs are those who are missing one or other of the Factors so they don't clot so good.

Last 27 November 2014 Nature put out an excellent multi-page supplement on Haemophilia and it's therapies which in contrast to the one on Liver Cancer, which I filleted last month, is not pay-walled.

It's not red or white; all or nothing. One hemophiliac may have a totally banjaxed Factor VIII, while another replaces glycine with valine at position 89 and can have something approaching a normal life.  Indeed your FVIII protein may be different from mine but both are sufficiently active for both of us to be in the normal range. The key theme in my Human Physiology course at The Institute is the idea of homeostasis and how amazingly good we are at it. Too sensitive a clotting cascade and we'll be getting deep-vein thrombosis every time we sit down to an episode of Neighbors rather than waiting for a long-haul flight.

There are +7 billion people on the planet today, of which about 180,000-350,000 have some form of hemophilia. To put that in some sort of utilitarian perspective 180 million people are infected with hepatitis C virus.  When the British Queen Victoria's fourth son was born with hemophilia in 1853, they could afford to keep him safe from slings and arrows and accidents but there was no effective medical intervention and he died (a trivial slip and fall led to a brain hemorrhage) at the age of 30. By the middle of the last century, hematologists knew enough about the process of clotting that they were able to concentrate the Factors by freezing whole blood and making injectible quantities available for therapeutic use.

That was better than nothing but the therapy was not without its problems. While the rest of us have a neat and delicate feedback loop to maintain the levels of Factor VIII and IX at a Baby-Bear just-right level, hemophiliacs were getting a gurt big lump of the stuff all at once. Normal Factors, along with pretty much all the biochemical bits and bobs in the circulation, have a turn-over time or a half life: old product is broken down and recycled and fresh stuff is made continuously. So Problem #1 for added Factor is that it doesn't last. Factor VIII is half gone in 8-12 hours, Factor IX lasts about 2x longer.  There is a lot of work going on in Big Pharma to extend these biological limits, so that the poor kids need to prick themselves less often. But it's been slow progress: the current best hope is Novo Nordisk's N9-GP which has a half life of 110 hours or 5x baseline. The longer time extensions all apply to Factor IX which is 1/6th the size of Factor VIII.  That's a bummer because 80% of clinical hemophilia is due to Factor VIII mutations.

As if getting a duff hand of cards from the genetic lottery wasn't bad enough, cock-ups in the blood transfusion industry allowed donors who were HIV positive to infect pretty much all the hemophiliacs who had access to Factor replacement therapy through the 1970s. They need so many 'units' of Factor VIII and so often that it was hard to avoid getting a contaminated batch. In the 1980s, after they'd started to screen for HIV, lots of hemophiliacs were infected with HCV because The Transfusion-Man failed to screen for that. Thanks a lot lads!  By 1989, molecular biologists had developed a genetically engineered form of F.VIII and in 1997 a GM F.IX was available. No chance of further viral contamination there. My tree-hugging anti-GM pals might reflect on that while they chant "Monsanto Bad Wakantanka Good" and dig up GM turnips in the remoter parts of agricultural research stations.

Another problem is the immune system. This teeters very day on a tightrope trying to recognise foreign proteins as potential, even probable, pathogens.  Believe me, it's wild world out there full of hostiles big and small - nematodes, bacteria, fungi and viruses - and you'd prefer that the immune system 'neutralises' pretty much anything it hasn't encountered before  . . . unless it's therapeutic Factor VIII.  But that much nuanced discrimination is often a bridge too far for a system working full time under unforgiving circumstances. This natural response is called factor inhibition and BigPharma is working in another part of the factory to develop anti-anti-bodies to neutralise or at least slow down the immune system to let artificial Factor VIII and IX carry out its essential task.

Finally we might ask why BigPharma is interested in hemophiliac treatment. It's not only about the money but a lot of it is sloshing about earmarked by medical insurers both private and socialist for treatment of hemophilia. In rough terms, a unit of Factor VIII costs $1.  For prophylactic dosage, an adult needs about 25 units per kilo body-weight or $1750 a go. 2x or 3x a week every week for 52 weeks a year that's the bones of $300,000 a year. If half the hemophiliacs have access to replacement therapy we're looking a retail price of $25 billion every year globally. In Ireland there are about 200 hemophiliacs, whose (€60m/yr) bills are picked up by the Health Service Executive. Only the hardest Utilitarian is going to ask what else could be achieved with that much money.

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