Cataclysmic shortages. Tainted supplies. There is a solution: artificial blood.
The nurses introduce me to a man I'll call Cappy, a 55-year-old barber with diabetes, arteriosclerosis, and a collapsed femoral artery that threatens to gangrene his left leg. He's sitting in a hospital bed, dressed in the humiliating garment of patients everywhere: a skimpy, washed-out floral-print gown that countless strangers have dribbled their fluids on, maybe even died in. It seems an intrusion even to look at him, much less speak; nevertheless, I ask how he's doing.
"I got a bum leg, yah," he says. "What can you do?"
Cappy isn't in pain exactly, yet even I can see that one of his legs is the wrong color: too pale, more white than pink. He has known for a while that this creeping numbness is a serious matter, and now that he's had an angiogram - a dye-stained X ray of his blood vessels in action - the doctors have told him it's surgery either way: restore the circulation or amputate the leg. Not much of a choice.
Photo by Suede
A 250-ml bag of Hemopure – the polymerized solution is three times more efficient than ordinary blood cells and has a three-year shelf life at room temperature.
Early the next morning, he's wheeled into the operating room, anesthetized, intubated, and hooked to a respirator, then shrink-wrapped in clear 3M plastic and covered with sterile drapes. In this state, he'll undergo a balloon angioplasty, the insertion of a steel-mesh stent to hold open the main artery running through his leg, a long-overdue plaque removal, and a bypass graft to replace a key section of the artery with a segment of vein from just beneath the skin of his thigh.
This operation isn't normally a huge bleeder - once the incisions are made, Cappy's vascular surgeon, Lewis Levien, moves along, meticulously tying off the large blood vessels and cauterizing the small ones as he goes. But something happens, as somethings often do in this business, and Cappy suffers two minutes of uncontrolled bleeding during the grafting process, then half an hour of slow seepage while the artery is closed off and checked, millimeter by millimeter, for leaks. Levien, a licensed pilot as well as a surgeon, has done this operation hundreds of times and remains cool throughout, yet after four grueling hours that are exhausting just to watch, the stapled-up leg has bled away nearly 2 liters.
And this is a problem, because an adult human body contains only 5 to 6 liters (9 to 11 pints) of blood. The loss of half of it is invariably fatal. To sustain life, blood must have five components: red cells to carry oxygen; plasma to carry nutrients and antibodies; pressure to force the flow of the other components and to drive the exchange of gases; platelets and clotting factors to seal up a wound; and white cells to examine and attack invading substances and organisms in a variety of ways. Cappy has lost all of these in more or less equal proportion. The white cells he can live without, at least for a while, and the body has a surplus of platelets that will ensure the scabbing and healing of the incision. Blood pressure can be boosted - and plasma replaced - with clear fluids like saline and ringers, which have been dripping into him since before the surgery began. But without the red cells, Cappy's blood has lost a third of its oxygen-carrying capacity, and this is serious business even for a healthy individual, which Cappy surely is not. He needs a red cell transfusion, and he needs it now.
But here lies another problem - we're in South Africa, where the human immunodeficiency virus has slipped into the veins of at least 4.5 million people. That's 10 percent of the population. Some estimates put it much higher, at 25, 30, or even 40 percent, and all studies agree that the numbers are climbing, making this country among the hardest hit anywhere. The result, in addition to the obvious misery and death, is a blood shortage of huge proportions.
Necessity breeds invention, however, and it can also cut through snares of bureaucracy. As Cappy's pale, anemic body is wheeled into intensive care, Levien tells the nurses there to "hang a bag of aitchbock." That's H-B-O-C, for hemoglobin-based oxygen carrier - the generic term for Hemopure, a therapeutic substance made by Cambridge, Massachusetts-based pharmaceutical firm Biopure and approved for use nowhere in the world except South Africa. This is artificial blood, and it's clean and pure and fresh from the tap - never touched by human hands or human pathogens. To collect Hemopure for an injured South African, you don't need donor drives or questionnaires or tourniquets or risk. All you need is a head of cattle.
Blood substitution has a colorful past, dating back at least as far as the mid-1600s, when English physicians injected sheep's blood into wounded soldiers in a vain and horrific attempt to save their lives. Animal-to-human transfusions were quickly banned because of the fatal immune reactions they triggered. But through the 19th century, doctors experimented with a variety of blood substitutes, including water, oil, and milk. At the same time, studies in human-to-human transfer continued sporadically, saving a life for the first time in Philadelphia in 1795. The success record remained spotty, with most recipients dying either of their injuries or from reactions to the foreign blood. Not surprisingly, the procedure was considered a dangerous last resort until the early 20th century, when the discovery and cataloging of the various blood types made it possible to match donors and recipients with reasonable - though by no means total - safety.
Today, Western countries transfuse blood in industrial quantities, pouring tens of thousands of units per day (1 unit equals 450 ml) into accident victims, surgery patients, and sufferers of assorted illnesses. In 2000, banks in the United States collected some 13 million liters from 8 million individual donors, for the benefit of about 4.5 million patients. Yet supplies that year were almost always short (only 3 percent of Americans donate blood, while 95 percent will use it at some point in their lives). Reserves often fell to a three-day supply - and occasionally to zero days, which resulted in the postponement of vital surgeries. A surge of volunteerism after 9/11 has boosted supply, increasing the average US reserve to about 10 days (or 50,000 patients). Given red blood cells' 42-day shelf life, however, anywhere from 3 to 8 percent of donated units are sent to the incinerator.
Of course, all this takes place against the constant background fear of contamination, not only from HIV and other viruses, but from drugs, toxins, and the infectious proteins that cause mad cow and other diseases. This means a lot of testing, which means the blood we get is never fresh, which means it doesn't work as well and carries a greater risk of side effects.
Blood shortages also threaten the stability of a multi-gigabuck industry. Today, patients are rarely infused with a donor's raw substance, unless they choose to freeze and store their own for medical or other reasons (think Olympics). Instead, donated blood is filtered and centrifuged into a variety of specialized products, including plasma ($195 per unit), clotting factors ($175 per unit), red blood cells ($225 per unit), and assorted proteins and immune factors, which wholesale for hundreds or thousands of dollars per milligram. That means every unit you donate can be repackaged to fetch $1,000. If you're prohibited from donating - as are Britons, South Africans, gay men, and other demographic groups - that's a blow to the system. A lifetime ban of a donor willing to give four times a year for 15 years amounts to 60 grand.
In an effort to smooth these bumps and to prepare for the worst, the Red Cross is creating a $50 million Strategic Blood Reserve, where universal donor O-negative red blood cell units can be frozen for up to 10 years. This requires laborious steps, such as replacing some of the water with glycerol antifreeze to prevent ice crystals from rupturing cells, but about 10,000 units were processed in 2001. Eventually, the organization expects to freeze 100,000. Still, there's no guarantee that the stored blood will be as effective as fresh, or that it will be 100 percent clean. Like Britain, the US may discover a lurking pathogen that would cast doubt over the entire supply.
To truly end blood shortages and the fears that help produce them, hospitals would need a fluid that's laboratory pure, universally compatible with any human blood or tissue type, and indefinitely storable at room temperature. Most important, it would have to perform the function of oxygen delivery, so far the most elusive function to mimic in efforts to create fake blood. Simply adding oxygen-carrying hemoglobin to a substance like saline won't work - the raw hemoglobin molecule turns out to be both short-lived and toxic to the kidneys and liver unless surrounded by the fatty envelope of the red cell. And numerous other creative workarounds - like encapsulating the molecules in tiny globs of fat or chaining them together into polymers - have failed. Oxygen and CO2 can be dissolved directly into droplets of liquid perfluorocarbon, which holds and releases the two gases about as efficiently as hemoglobin does; when oxygenated, this liquid is even breathable - remember the rat in The Abyss ? This approach too, however, produces side effects, from toxicity to allergies to exhaling an ozone-depleting gas.
Only one oxygen-carrying blood substitute has ever been approved by the FDA. That was Fluosol, a perfluorocarbon additive developed in the US and marketed by Japan's Green Cross corporation from 1989 to 1993, during which time it was infused into some 13,000 patients in the US annually. Unfortunately, Fluosol was a frozen, two-part drug that had to be thawed and mixed immediately prior to use, and in large doses it required patients to breathe pure oxygen (potentially toxic) for the weeks it took their natural blood supply to recover. Meanwhile, doctors had to keep pumping the stuff in every 12 hours or the patient would die, bloodless in a cloud of exhaled fluorocarbons. Fluosol was eventually pulled off the market.
That hasn't stopped others from trying. Today around 10 companies are pushing blood substitutes through the FDA approval process. Among these, publicly traded Biopure is the clear front-runner, with a polymerized hemoglobin solution called Hemopure derived from the blood of slaughtered beef cattle. Using cows as a source of hemoglobin may be unnerving, but Biopure's Brad Miles dismisses concerns. "The cows we use come from a managed herd in Michigan, where we know everything that ever happens to them. Anyway, we've demonstrated that our purification process screens out any bacteria and viruses, as well as prion pathogens like mad cow."
Too big to pile up in the kidneys and too small to trigger an immune reaction, Biopure's polymer appears to be the Baby Bear of the HBOC world: just right. If stored at room temperature in light-proof pouches, Hemopure has a three-year shelf life and an excellent clinical reputation. A veterinary product, Oxyglobin, has been approved in the US and Europe, and Hemopure, the human formula, has been used in 40 compassionate-use cases in America. In a trial involving 350 patients in the US, 96 percent avoided red cell transfusions they would have required on the first day after surgery; over a period of six weeks, 60 percent never needed transfusions, relying instead on Hemopure.
And the drug has completed its final approvals in South Africa, where surgeons now use it daily in patients like Cappy, who are at risk for heavy blood loss. I'm there with Cappy the night before the surgery when he scribbles his signature on a consent form stating he's willing to receive the product if he needs blood. He knows that HBOC is new, carries some risk, and evokes a Frankensteinian creepiness, though when questioned about it, he seems flip. "It's germ-free and something like that, yah." (People here don't say yes, or even yeah, preferring a variant of the German ja.) "I think it's a good thing, it sounds good," Cappy says. "I'm gonna try it."
The future doesn't appear on earth all at once the way a stock offering might, or even roll around with the rising sun. Instead, it blossoms in discrete locations, spreads in ponderous waves, and fills the wind with sporelike memes than can settle and bloom without warning. These outbreaks are hardly random - Tokyo and Silicon Valley and lower Manhattan are more prone to them than places like Des Moines - but when it comes to the transfusion of blood, the future has skittered down to the unlikely South African province of Gauteng, a hilly, semiarid region 1,500 miles south of Olduvai Gorge.
With vast mineral wealth and a mixed economy including agriculture and industrial machinery, tiny Gauteng - about the size of Connecticut - is the engine that accounts for 25 percent of the economic output of the entire African continent. And yet despite its wealth and mild climate, it is a land of polar extremes. With a population of 2.5 million middle-class whites speaking Afrikaans and English, and 5 million mostly poor blacks speaking Zulu and other Bantu languages, it's both the cradle and crypt of apartheid.
While Gauteng is the engine of Africa, Sandton is the engine of Gauteng. It is in this posh Joburg suburb that Netcare - the world's only licensed user of Hemopure - has its headquarters in a chic little office tower behind the stock exchange, alongside the local telegiants, Vodacom and iafrica.com. Both an insurance company and a specialist in the turnaround of ailing medical facilities, Netcare owns a third of all private hospital beds in South Africa.
Cappy lies in one of them, tethered to various machines in the recovery ward of Milpark Hospital. The jewel of Netcare's crown is Milpark's huge trauma center and ICU, a 90-bed facility serving more than 8 million subscribers, not only within South Africa but from many surrounding countries as well. To an injured Zimbabwean, whose country is nearly as ravaged by AIDS as South Africa, the prospect of air evac to Milpark may be considerably more appealing than any of the local alternatives. In fact, because South Africa is the most advanced nation on the continent, it's a popular destination for elective surgery as well - so much so that Netcare has its own travel bureau for customers.
Post-surgery, Cappy receives his first dose of secular sacrament: an IV bag of watery, nearly odorless fluid with the texture and dark purple color of a pinot noir. To put it mildly, Hemopure doesn't look like something you'd want dripping into your veins. The very idea is disturbing and unnatural, in the same ghoulish way that the first transplanted hearts and kidneys must have seemed. The drip is also surprisingly slow, taking two hours to deliver 100 ml of product. "The slower we add it, the fewer side effects we observe," Levien tells me.
Cappy wakes up a few times, drinks a little water, visits briefly with his family. The ordeal has exhausted him, and he doesn't want to talk. I don't press. What's it like? How does it feel? Cappy's actions speak for themselves. He sleeps the afternoon and evening away.
"His body will adjust chemically to the anemia and start producing additional red cells," Levien explains, "but this HBOC will bridge him through the next few days. We want a well-oxygenated patient for the healing process." A guarded gentleman on the slow side of 50, Levien can seem worn-out, like someone whose world has been upended a few times too many. "We're very cautious," he says. "This isn't a battlefield." But he has put more HBOC into more patients than any other doctor, and when he talks about it, optimism surfaces. His use of Hemopure has been invariably successful.
The next day, Cappy's looking much better, even smiling a bit. "Yes, I feel well. It's just the cuts and stuff are sore, you know?" Cuts indeed: The stapled incision runs the whole length of his leg and is bone-deep in places. As for the symptoms of anemia, Cappy pleads ignorance. Shortness of breath? Weariness? Inattention? "No, no, just sore after the operation." As for side effects from the HBOC: "Well, I don't think so. How's it supposed to feel? Being one of the early customers for this thing, well, it's exciting. We'll see how it goes, yah?"
Meanwhile, other patients on the ward are in various stages of recovery from HBOC-assisted surgery. Margaret, a housekeeper from Soweto, has undergone a partial mastectomy and has a hemoglobin level that, according to her oncologist, "ought to have her in ICU." Instead, she's up and about, obviously weary though by no means knocked out. "I've been exercising just now," she huffs. "There's no side effects that I can say. Nothing I felt or seen, like with the chemo."
In a way, this is disappointing. I want to hear that the HBOC feels tingly going in, that the patient experiences an immediate rush of energy. Certainly, the visible effects are striking: Before the IV bag is even a third of the way empty, people tend to sit up and begin speaking in more than monosyllables. But what does it feel like? Nothing.
In most cases, anyway. Elsewhere on the ward, Rebecca is complaining of difficulty swallowing - an occasional side effect of Hemopure. "I just can't get my food down," she explains. She also looks a bit yellow around the skin and eyeballs. This "jaundice" is somewhat alarming in appearance, though actually has nothing to do with liver or kidney problems. The Hemopure molecule simply diffuses out into the tissues, occasionally dyeing them for a day or two. At higher doses, eyeballs can start taking on a bloody, purplish appearance. "I've had this operation before," Rebecca tells me. "I'm a mess, frankly, but it doesn't really feel different with this chemical involved."
Having polymerized hemoglobin in her bloodstream is different, however. It's more efficient, for one thing, absorbing and releasing oxygen three times faster than blood cells can. "Even after our training," says Levien, "many doctors make the mistake of thinking of this as a one-for-one trade with a pint of blood. It isn't. It's a highly concentrated drug." For another thing, it's available for oxygen transport the moment it enters the bloodstream, whereas banked blood doesn't start working for at least six hours. Also, it soaks up nitric oxide - a process that can raise blood pressure and cause the sort of abdominal cramps and dysphagia Rebecca reported.
Hemopure is also less viscous than blood, and because it's made up of small molecules, it not only travels past obstructions that would block a red cell, but also, in a wholly novel way, carries oxygen directly into the tissues. And that - not the bloodstream itself - is where the oxygen ultimately needs to go. Blood gas is irrelevant - if successful, HBOC drugs could well drive the adoption of a "tissue oximeter" (instead of the standard pulse oximeter) as the final measure of a patient's respiration. And once you accept this tissue-ox concept, a whole host of other HBOC applications will begin to suggest themselves, from the reversal of carbon-monoxide poisoning to the travel-packing of live organs for transplant.
Perhaps the most important difference between Hemopure and ordinary blood is the way Hemopure interacts with the body's red cell gas transport systems. "Since blood plasma is normally a barrier to oxygen transfer," Levien says, "red cells can release oxygen only when they're in direct contact with the capillary membrane. With hemoglobin dissolved directly into the bloodstream, on the other hand, the red cells can suddenly exchange oxygen with the plasma itself. It's the difference between a truck that has to stop at your front door and one that can hand its cargo off to pedestrians in the street who will carry it the rest of the way."
Even at very low doses, when the HBOC molecules are moving a tiny fraction of total blood oxygen, they serve this unloading function, allowing oxygen to penetrate tissues more efficiently. A similar effect is observed in racehorses and greyhounds and extreme human athletes when red cells rupture under distress, spilling hemoglobin directly into the bloodstream. "We used to think this condition was pathological," Levien observes with a hint of a smile, "but now I'm not so sure. It's bad for the kidneys, yes, but it would be a handy adaptation to extreme exercise. The body's own HBOC."
Does this effect make Hemopure an appealing - if illegal - performance enhancer? "Unfortunately, yes," Levien says. "The potential for abuse is enormous." Already, Biopure's veterinary product, Oxyglobin, is being used by cyclists, many of whom are accustomed to taking some very scary stuff. HBOC, it turns out, is sneakier than erythropoietin, the scandalous star of the 1998 Tour de France. The latter increases red cell count - a warning flag to race committees everywhere. Hemopure, on the other hand, doesn't reveal this increase till days after the race, while its oxygen-transport improvements are immediate and undetectable. Guess what the next major sports scandal will be? The purple-eyed winners can tell you.
In a running- and biking-obsessed country such as South Africa, it isn't at all difficult to meet a guy who knows a guy who knows a guy. I'm cautiously put in touch with a bicyclist I'll call Chris, who seems nervous about discussing the issue and yet bursting with the need to. "I've used Oxyglobin in competition," he tells me. "I get some abdominal cramps and occasional flushing, which I don't like. But it improves my peak performance considerably."
"That's not surprising," says Biopure's head of corporate communications, Douglas Sayles. "We have anecdotal reports of its use in animal racing as well. The company does not condone that, obviously."
Although the clinical use of HBOC has just begun - about 100 South African patients have been infused since the product was approved in the country - demand there is expected to surge to about 100 units a day by next year. In anticipation of US approval, perhaps as early as 2003, and next a greenlight in Europe, Biopure has upgraded its Cambridge plant for an annual capacity of 100,000 units and is breaking ground on a 500,000-unit facility in South Carolina.
For now, Biopure is providing Hemopure to South Africans like Cappy free of charge, in exchange for the "education" the patients provide to the medical community. Eventually, the product will be priced at $150 per unit, comparable to the cost of blood. Commercial similarities end there though. The inherent waste and logistical headaches of blood banking mean that red cell units are often sold at a loss, with the profits being made on other components. If the handling of red blood cells could be replaced with easy movement of a room temperature-storable product promising a shelf life of years rather than weeks, the dollar savings could be enormous. As Biopure's CEO Carl Rausch says of the Red Cross, "They have to type test, cross test, viral check - every two weeks! This changes the paradigm of managing blood." Plus, as other blood components are increasingly replaced with recombinant vat product, banks are losing an important source of revenue, which could force an increase in the cost of red cells.
In addition, artificial blood has the potential to provide an entirely new service: transfusion in forward areas, from battlefields to ambulances, from rural clinics to cruise ships and oil rigs. The Netcare paramedics I talk to are thrilled by the prospect. "At our level, the response level," one tells me, "medicine fundamentally hasn't changed since the defibrillator. Once the patient arrests we still have 98 percent mortality, yah. Anything we can do in the golden hour to improve oxygen levels is bound to have an effect on survival."
But the final word on Hemopure is Cappy's. I ask him how he feels about being a guinea pig for US drug companies. "Listen," he says, "my foot hurts. It's got blood in it finally, so now it can hurt. This stuff, this - whatever - this cow blood, we've taken it. If it's in, it's in, yah?"
Words of wisdom indeed, and a hint that others will no doubt overcome their yuck reflexes too and join Cappy at the receiving end of an HBOC tube. In fact, we may all be gathered at some point, connected in a time of crisis by that strongest of bonds: common blood. Even if it does come from a slaughterhouse.
How Spilled Blood Saves Lives Attempts to work around blood shortages are myriad and clever - ranging from making smaller incisions during surgery to prescribing pre-op drugs that stimulate the creation of new red cells. Most shocking for the squeamish is a practice called "blood salvage," which is used frequently for treating Jehovah's Witnesses, who refuse transfusions, as well as for ordinary patients. The principle: Why let a good thing go to waste? The technique: Sop up, suction, filter, and centrifuge a patient's own spilled blood, and pour it right back in again. In South Africa, according to Netcare doctor Efraim Kramer, nurses sometimes even wring out sponges and drapes into what looks like a dog's water dish, then process the drippings. Despite the initial ick factor, it turns out the technique is as safe as Red Cross methods of collection, providing a fresh product for immediate use. It's also good medicine. According to Kramer, recycling blood, rather than introducing old batches from donors, reduces serious complications and improves overall survival by 4 percent. - W.M.
