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A friend at a dinner party once turned down the bread basket because she was "type A, and grains don't agree with her blood." I nodded, passed the butter, and spent the rest of the meal thinking about lectins instead of listening to the conversation. Occupational hazard. The blood type diet has been around since 1996, when naturopath Peter D'Adamo published Eat Right 4 Your Type [1]. Its premise: your ABO blood type reflects your ancestors' diet, so eating in accordance with your type optimizes digestion and health. Type O, the "hunter," should eat like a caveman: high protein, minimal grains. Type A, the "agrarian," should go largely vegetarian. Type B gets dairy. Type AB gets a little of everything, marketed as the "enigma" for reasons that say more about branding than biology. The mechanism, as advertised The theory rests on lectins: proteins found throughout the plant kingdom, concentrated in legumes and grains, that bind to carbohydrate molecules. D'Adamo's claim is that dietary lectins interact with the antigens on your red blood cells the way incompatible blood interacts in a transfusion reaction, causing agglutination, clumping, and a cascade of downstream health problems specific to your type [2]. If you work in transfusion medicine, you already know where this goes wrong. What agglutination actually requires Agglutination in a clinically meaningful sense requires antibody binding to a compatible antigen, at a concentration and in an environment that supports crosslinking. It is not a generic hazard that any given protein produces on contact with blood. The lectin literature bears this out: a systematic review of blood type diet claims found no controlled evidence that dietary lectins clump blood cells inside the body in a type-specific way [3]. Most food lectins denature with cooking. Of the ones that survive digestion intact, the review found the overwhelming majority react with all ABO types indiscriminately, not selectively with one [3]. There is a small, real exception: raw legumes contain lectins with some blood-type-preferential agglutinating activity in vitro [4]. But "some lectin behaves selectively in a test tube" is a long way from "your dinner is attacking your blood type." What the trials actually show A few groups have tested the diet's health claims directly rather than the mechanism. The most-cited systematic review, Cusack et al. in the American Journal of Clinical Nutrition, found that while several of the individual "type" diets were associated with favorable changes in metabolic risk markers, the effect held regardless of the subject's actual blood type [3]. In other words: the Type O diet made people healthier whether or not they were Type O. The diets are, structurally, healthier eating patterns. Less processed food, more vegetables, controlled portions. People who follow any of them tend to do better than people who don't, and the ABO matching adds nothing measurable on top of that [3]. A separate analysis, Wang et al. in PLoS ONE, looked directly at ABO genotype against the diet's proposed cardiometabolic outcomes and found no interaction: type didn't predict which diet worked better for whom [5]. Why it persists anyway None of this has hurt sales. The obvious answer is that personalization sells better than generic advice, and blood type is one of the few pieces of biology most people can actually name about themselves. "Eat less processed food" is true and unsatisfying. "Eat less processed food because you are Type A" is a story, and stories are what people remember at dinner parties. There's a less cynical read too. We want our biology to explain us: why we feel good after some meals and sluggish after others, why one relative thrives on a diet that wrecks another. ABO type is legible in a way gut microbiome composition or polygenic metabolic risk isn't. It's one letter, drawn on a card in your wallet, and it feels like it should mean more than it does. It doesn't. Eat the vegetables. Skip the antigen mapping. References 1. D'Adamo P, Whitney C. Eat Right 4 Your Type. G.P. Putnam's Sons; 1996. 2. Nachbar MS, Oppenheim JD. Lectins in the United States diet: a survey of lectins in commonly consumed foods and a review of the literature. Am J Clin Nutr. 1980;33(11):2338-2345. 3. Cusack L, De Buck E, Compernolle V, Vandekerckhove P. Blood type diets lack supporting evidence: a systematic review. Am J Clin Nutr. 2013;98(1):99-104. 4. Sharon N, Lis H. History of lectins: from hemagglutinins to biological recognition molecules. Glycobiology. 2004;14(11):53R-62R. 5. Wang J, García-Bailo B, Nielsen DE, El-Sohemy A. ABO genotype, 'blood-type' diet and cardiometabolic risk factors. PLoS ONE. 2014;9(1):e84749.

The patient is a composite, built from enough cases to be nobody in particular: an elderly man admitted with a colonic obstruction, febrile, blood cultures eventually growing a gram-negative rod. His chart says A positive. It has said A positive for decades, through two prior admissions and one prior transfusion. The type-and-screen that comes back this time says otherwise. The forward type shows both A and a weak but unmistakable B reactivity. The reverse type, his own serum against reagent cells, still shows anti-B, exactly as it should for a lifelong group A patient. Forward and reverse disagree. Someone on the bench who has seen this before doesn't reach for a rare subgroup workup. They reach for the chart, note the fever and the bowel pathology, and write "acquired B" before the second tube has finished spinning. He is still, genetically, group A. Nothing about his ABO gene has changed. What's changed is what a bacterial enzyme has done to the surface of his red cells, and that distinction, between what your genes say and what your cells are currently showing, is the whole subject of this post. Genotype and phenotype, briefly Your ABO genotype is fixed at conception: the specific alleles you inherited, encoding glycosyltransferase enzymes that add either N-acetylgalactosamine (making A antigen) or galactose (making B antigen) onto a common precursor structure on the red cell surface. Your ABO phenotype is what a lab actually detects: the antigens expressed on your cells, tested by forward typing, and the antibodies circulating in your plasma against the antigens you lack, tested by reverse typing. In the overwhelming majority of people, genotype and phenotype agree completely, which is why we treat "blood type" as a fixed, inherited fact roughly on par with eye color. Most of the time it is. It's just not guaranteed to be, and the exceptions are where transfusion medicine gets interesting. How the mismatch happens Acquired B is the cleanest example because the mechanism is fully worked out. Certain gram-negative bacteria, often colonic flora that have gained access through a compromised gut wall from a tumor, obstruction, or infection, carry a deacetylase enzyme. That enzyme strips the acetyl group off the terminal sugar of the A antigen, N-acetylgalactosamine, converting it to galactosamine [1,2]. Galactosamine happens to be structurally close enough to galactose, the terminal sugar that defines the B antigen, that commercial anti-B reagent cross-reacts with it [1]. The cell hasn't started making B antigen. It's wearing a chemically modified version of its own A antigen that a reagent mistakes for B. Pull the source of bacterial exposure, whether by treating the sepsis or resecting the tumor, and the discrepancy resolves on its own, typically within weeks [3]. Genotype never moved. Phenotype took a temporary detour. Post-transplant chimerism works differently but lands in the same place. A patient who receives an ABO-mismatched hematopoietic stem cell transplant will, over the course of engraftment, gradually stop typing as their native blood type and start typing as their donor's. Eventually the genotype itself has changed, at least in the hematopoietic compartment: the red cells being produced are now genetically the donor's. This one isn't a transient artifact to be explained away. It's a real, durable shift, and it means "blood type" for a post-transplant patient has to be tracked as a moving target rather than looked up once and filed away [4]. A third category lives entirely on the genotype side: weak ABO subgroups, where an inherited variant allele produces a glycosyltransferase with reduced enzymatic activity. The antigen is present, just sparse enough that forward typing looks weak, ambiguous, or occasionally falls out as an apparent O in a person who is not, in fact, group O. No bacteria involved, no transplant involved. Just an inherited enzyme that's technically functional and practically underpowered. Why it matters beyond the interesting case report Every one of these scenarios is a reminder that "check the type" and "trust the historical type" are not the same instruction, and blood banks build entire policies around knowing when to prefer one over the other. A patient with a documented history of acquired B doesn't need a lifelong flag reclassifying their type; they need the discrepancy recognized as transient and resolved on the next clean sample. A post-transplant patient needs active tracking through engraftment, because giving blood matched to their pre-transplant genotype can become the wrong call partway through their course. A weak subgroup needs to be distinguished from acquired B and from genuine group O, because the transfusion consequences of getting that wrong are not symmetric. None of this is exotic. It's the ordinary, unglamorous discipline of not assuming a chart from three years ago is still telling you the truth. Where sequencing fits Serology answers what the cells are doing right now. It doesn't always answer why, and in ambiguous cases, that gap matters. Genotyping resolves the categories serology can't cleanly separate: distinguishing a weak subgroup from an acquired phenomenon from early mixed-field chimerism, in a single pass, without waiting for an infection to clear or a repeat sample to confirm a trend. That's the appeal of ABO genotyping as a clinical tool, and it's the part of this space I've been spending the most time in lately. More on that as the work develops. The identity question People treat blood type the way they treat a birthday: fixed, inherited, a fact about you that predates memory. Mostly that's fair. But "mostly" is doing real work in that sentence. Somewhere in a transfusion service right now, a phenotype is quietly disagreeing with a genotype, and the discrepancy is not a lab error to be explained away so much as a reminder that even the facts we consider most fixed about our own biology are, on some timescale, conditional. References 1. Blood Bank Guy Glossary. Acquired B Antigen. bbguy.org. 2. Judd WJ, Friedman BA. The acquired B antigen phenomenon. ASCP Check Sample Program, Immunohematology No. 1-82; 1975. 3. Campbell TA et al. Acquired B antigen: an ABO typing discrepancy successfully reversed by transfusion with type A red blood cells. Transfusion. 1980;20(3):345-348. 4. Resolution of an unexpected ABO typing discrepancy in a 9-month-old patient with juvenile myelomonocytic leukemia. Clin Case Rep. 2020.

Families who request directed donation from an “unvaccinated” donor believe they are choosing the safer option. The literature says the opposite. Directed donations, particularly from first time donors recruited specifically for the occasion, carry higher rates of infectious disease marker reactivity than units from repeat community donors. The donor pool people trust the most, because they know the person, is measurably less safe than the anonymous pool they're trying to avoid. That paradox sat quietly in the guidelines for years, cited in position statements and discouraged in policy language, without much data on what actually happens when a request like this proceeds anyway. A two year single center series out of Vanderbilt, published this year in Transfusion, gives us that data. It's worth sitting with. What They Found Between January 2024 and December 2025, the VUMC blood bank received 144,856 total blood product units. Of those, 48, or 0.03 percent, were directed donor units collected specifically because a patient or family refused standard inventory over concerns about vaccinated donors. Every single directed donation in the study period, with no exceptions for rare blood types or other medically recognized indications, was motivated by this concern. Those 48 units covered 15 patients. Median age was 17, ranging from 4 months to 73 years, and 60 percent were pediatric. The requests weren't rare and holding steady either. They climbed from 4 patients in 2024 to 11 in 2025. Thirteen of the 15 patients were transfused at least one directed unit. And 7 of the 15, nearly half, had at least one unit collected on their behalf that was never actually transfused to them. Those units didn't vanish. Most were released back into general inventory. Someone drew blood from a specific person, for a specific patient, under a specific belief about safety, and then that blood went to a stranger anyway. That's not a rare edge case in this series. It's closer to the norm. Where the System Broke Here is the finding that matters most to me as a transfusion medicine physician: of the 15 cases, only 1 had a documented ethics consultation. Only 1 had transfusion medicine notified before the directed unit arrived at the blood bank, and even that notification came after the perioperative service had already approved the request going forward. This isn't a story about families making an uninformed choice in a vacuum. It's a story about a workflow. Requests here were routed directly from a family or a primary clinical team to an external blood donor center's online form, entirely outside the consultation structure that exists precisely to handle requests this ethically and medically complicated. By the time anyone with transfusion medicine expertise heard about it, the decision had usually already been made. It didn't have to go this way. Mayo Clinic's Bloodless Medicine and Surgery Program uses structured shared decision making for exactly this kind of request, and most families end up accepting standard blood products through that process. Mayo has since restricted directed donation absent a genuine medical indication. Seattle Children's Hospital built a similar structured consultation model, pairing transfusion medicine with ethics, for pediatric cardiac surgery cases with vaccine related concerns, and it worked there too. The difference between those institutions and this series isn't the families. It's whether anyone with the right expertise was in the room before the blood was drawn. Harm in Both Directions The clinical consequences in this series are not abstract. One patient's hemoglobin fell to 5.9 g/dL with symptomatic anemia while transfusion was delayed awaiting arrival of directed units. That same patient later received a transfusion at a hemoglobin of 9.2, a clear deviation from institutional guidelines, because the clinical team didn't want the directed unit to go to waste after all that effort to obtain it. Sit with that sequence for a second. A patient was harmed by the delay. Then a guideline appropriate threshold was overridden to avoid wasting a unit that should never have been the deciding factor in the first place. The instinct to avoid waste, once the unit exists, quietly overrides the standard of care that exists to protect the patient. A second patient developed hemodynamic shock with a hemoglobin nadir of 3.6 while awaiting directed blood. Two additional patients had surgery delayed or cancelled entirely because of directed component logistics. Four of fifteen patients, more than a quarter of this small cohort, experienced a documented adverse clinical or operational event tied directly to this workflow. Outcome Patients Received at least one directed unit 15 Transfused at least one directed unit 13 (87%) Had at least one unit collected but never transfused to them 7 (47%) Clinical deterioration while awaiting directed units 2 (13%) Transfusion deviating from institutional guidelines 1 (7%) Surgical delay or cancellation 2 (13%) Ethics consultation documented 1 (7%) Transfusion medicine notified before unit arrival 1 (7%) The Weight Falls on Children Nine of the fifteen patients in this series were minors. Among pediatric patients, surrogate decision making applied in 100 percent of cases, compared to 17 percent of adult cases. These are children absorbing the downstream consequences, clinical and logistical, of a belief about vaccination status that they had no part in forming and no ability to consent around. The ethical weight of that imbalance is hard to overstate, and it's the piece of this paper I keep returning to. A Familiar Failure Mode I've written before about laboratory medicine as a kind of governance layer, the expert checkpoint that's supposed to sit between a high stakes request and its execution, whether that request involves an unvalidated algorithm or a unit of blood. This series is that same failure mode wearing a different face. An ethically loaded, medically consequential request bypassed the expert consultation layer almost entirely, not because the layer didn't exist, but because the workflow routed around it. Governance failures rarely look like a single bad decision. They look like a form that lets you skip the conversation. Where This Leaves Us The authors propose a fix that sounds almost too simple: mandatory transfusion medicine consultation for every directed donation request, before collection proceeds, replacing what is currently an optional and easily bypassed step. Mayo and Seattle Children's suggest that when this consultation happens, most families accept standard products anyway. That's an encouraging signal, but it doesn't fully resolve the harder tension underneath this paper, the one between respecting a family's autonomy to make decisions about their own care and preventing exactly the kind of harm this series documents. A mandatory consult can close the routing gap. It can't, by itself, tell us how to balance those two obligations when a family still says no after hearing everything transfusion medicine has to say.

I knew Wisconsin had hard water before we moved here — everyone warns you about the white crust that builds up on faucets, the way soap won't quite lather right, the kettle that needs descaling every few weeks whether you want to deal with it or not. What I didn't expect was how much I'd find myself thinking about it on a quiet Saturday afternoon, half-bored, half-curious, turning over a question I hadn't really asked before: does any of this actually do anything to me? Hard water, by definition, is just water carrying more dissolved calcium and magnesium than usual — picked up as it filters through limestone and rock on its way to your tap. And calcium is, of course, the mineral I spend a fair amount of my professional life thinking about, just usually in the context of a patient's blood draw rather than my own kitchen sink. So the question followed naturally: if I'm drinking measurably more calcium every day than I was in my old soft-water house, is more of it ending up in my blood? The Body Doesn't Work That Way The honest, slightly anticlimactic answer is no — and the reason is one of the more elegant pieces of human physiology. Serum calcium isn't a passive reflection of however much calcium you happen to eat or drink on a given day. It's tightly, almost stubbornly regulated by a feedback loop involving parathyroid hormone, vitamin D, and the kidneys, all working continuously to hold your blood calcium inside a narrow range regardless of what's coming in from your diet. Drink more, and your body simply absorbs and excretes accordingly, defending the same set point it always defends. This isn't just theoretical. A Swedish study comparing people living in hard-water and soft-water regions looked directly for a correlation between calcium and magnesium levels in drinking water and the corresponding levels in serum — and found none. The water mineral content moved. The blood mineral content didn't follow. Homeostasis, doing exactly what it's supposed to do. But "no change in serum calcium" doesn't mean nothing happens at all — it just means the action shifts somewhere else. A small trial gave healthy young men a single glass of calcium-rich mineral water and tracked their bloodwork over the next few hours. Serum calcium, predictably, barely budged. But parathyroid hormone dropped significantly, and a marker of bone resorption fell right along with it. The body didn't need to raise blood calcium because it had just gotten a supply from the gut — so it dialed back how much it was pulling out of bone to maintain the same number. One glass of water, one afternoon, and you can already see the lever moving. So if hard water isn't raising anyone's blood calcium, the question becomes: does it matter for anything else? Where the Real Signal Shows Up It turns out the more interesting story isn't in serum calcium at all — it's in bone, and specifically in fracture risk, measured over years rather than in a single blood draw. A 2026 ecological study out of England found that neighborhoods with harder water had meaningfully fewer hospitalizations for childhood fractures than neighborhoods with soft water, even after accounting for the usual sociodemographic confounders. Norwegian researchers, looking at hip fractures in older adults, found a related pattern: lower calcium and magnesium in municipal water tracked with lower bone mass density and higher fracture incidence. That's a real, if quiet, signal — and it makes some biological sense. If chronic, low-grade mineral intake nudges PTH down just slightly over years and decades, the downstream effect is less ongoing resorption from bone to maintain serum levels. Nobody's blood calcium moves. The skeleton just quietly gets to keep slightly more of what it already has. But It's Never Just Calcium Here's where the story gets messier, in the way real epidemiology usually does. Hard water isn't a single-ingredient exposure — it's calcium and magnesium, almost always together, in ratios that vary by region and geology. The same Norwegian research group that found the calcium-fracture association also found that it depended heavily on what else was in the water; once they accounted for other minerals, the calcium signal alone wasn't clean or independent. You can't pull calcium out of "hard water" and credit it alone for what the studies are finding. Whatever benefit exists is probably shared, tangled, and not easily assigned to one element over the other. Which raises a natural next question: if it's not clearly calcium doing the work, what happens when you study calcium supplementation directly? The Calcium Supplementation Letdown Not much, as it turns out — at least not in the way most people assume. Systematic reviews of calcium supplementation in adults have found, at best, modest gains in bone mineral density: low single-digit percentage improvements at the hip, spine, and forearm, even at fairly substantial daily doses. One major review concluded there was no clear evidence that increasing dietary calcium intake actually lowers fracture risk at all. The mineral that seemed like the obvious hero of bone health, taken as a standalone pill in adulthood, just doesn't move the needle the way the supplement aisle would have you believe. That's a genuinely useful correction to a very widespread assumption — but it also means the hard-water fracture data probably isn't a calcium story either. Magnesium's More Promising, Less Finished Story So I went looking at magnesium on its own, and found a more encouraging — if still unfinished — picture. A 2021 systematic review found that higher magnesium intake was associated with increased bone mineral density specifically at the hip and femoral neck. Small clinical trials back up a plausible mechanism: magnesium supplementation in postmenopausal women has been shown to lower parathyroid hormone, raise markers of bone formation, and lower markers of bone resorption — the same hormonal lever that chronic mineral exposure from water seems to be quietly pulling. What's missing is the big, definitive trial: a large, long-term, fracture-outcome study in older adults that could say, with real confidence, "magnesium supplementation prevents fractures." That trial doesn't exist yet. What exists is a coherent mechanism and some encouraging early biomarker data — promising, but not proven. Two Different Stories, One Word So "hard water" turns out to be two separate stories wearing the same name. The calcium half looks like it matters most early — in childhood and adolescence, when bone is actively being built and every bit of mineral exposure has more to work with. That window is the one with the clearest evidence, and it's also the one I've already missed; I moved to Wisconsin at 41 and a half, well past peak bone accrual, with whatever skeleton I'd already built. The magnesium half tells a different, more open-ended story — one that may still have something to offer people my age and older, as the supplementation evidence slowly matures. I won't get the childhood benefit of this water. I might still get something from what's dissolved in it now, if the early signals hold up. Mostly, though, what stays with me is the bigger and slightly strange realization underneath all of it: something as ordinary as where you happen to live — the geology under your house, the minerals leaching into your tap water — has been quietly shaping human skeletons for as long as people have been drinking from the ground. I only thought to ask about it because I moved somewhere new and noticed the kettle scale. Most people never think to ask at all.

Microplastics are having a moment. They've turned up in blood, in placentas, in breast milk, and, most alarmingly, in a 2024 NEJM paper that's done more to shape the public conversation than almost anything else in this space, in carotid artery plaque, where their presence correlated with a higher rate of cardiovascular events. Here's what's actually established: microplastic particles are measurably present in human tissue and blood, and we absorb them through what we eat, what we breathe, and what touches our skin. That part is real. Here's what isn't established: whether any of it matters. There's no dose-response curve. No outcome data tying a given blood concentration to a given health effect. No consensus on whether the microplastics circulating in your blood on a Tuesday afternoon bear any meaningful relationship to the total burden sitting in your tissues. We have exposure. We do not have consequence, not yet, not with the kind of evidence that lets a clinician make a recommendation. That gap is exactly the space a wellness industry moves into fastest. Uncertainty reads as opportunity. So when a paper crossed my desk this year claiming that therapeutic plasma exchange can lower your circulating microplastic burden, I wanted to like it. I run an apheresis clinic. I would love a legitimate new indication. I read the methods first, the way I always do. What They Did Weinstein and colleagues, publishing in the Journal of Clinical Apheresis in 2026, tested 114 patients undergoing 174 single-plasma-volume TPE procedures on a Spectra Optia system. Blood was drawn immediately before and after each procedure and tested for microplastic particles using PlasticTox, a proprietary assay that involves drying a blood sample on a card, mailing it to a central lab, staining the isolated particles with Nile Red, and counting them under fluorescence microscopy. The procedures took place in functional medicine outpatient clinics. The indications were longevity support, postural orthostatic tachycardia syndrome, myalgic encephalomyelitis, and long COVID, none of which are established indications for TPE by any apheresis society guideline I'm aware of. No IRB approval was sought, because the authors classified this as normal-course-of-care data collection rather than research; consent was a checkbox on the standard TPE consent form, agreeing that results could be used anonymously in publications. The Number That Should Stop You The topline result, stated plainly: TPE lowered circulating microplastic counts, but only in patients who started with a lot of them. Below a certain threshold, TPE made things worse. Starting MP (per 100μL) Pre-TPE mean Post-TPE mean p-value 0–9 4.4 14.4 <0.001 (increase) 10–19 13.8 11.7 0.062 (no change) 20–29 23.6 16.1 0.040 (decrease) ≥30 52.2 21.1 <0.001 (decrease) Read the top row again. Patients who started with the lowest microplastic burden had over three times as many circulating particles after the procedure meant to remove them. That's not noise; the p-value is under 0.001. The explanation is almost certainly mechanical rather than biological: the apheresis tubing set and fluid bags themselves shed microplastic particles into the circuit as it runs. The paper's own tubing measurements bear this out: meaningful particle counts in the priming saline before it ever touched a patient. At low starting burdens, the plastic you're being infused through outpaces whatever the procedure removes. Only above roughly 30 particles per 100μL does removal clearly win. Who's Selling This Seven of the paper's thirteen authors are affiliated with Circulate Health, a company that provides contract TPE services to private clinics. The remaining four are officers of the clinics where the data were collected. I'm not raising this to imply fraud; the data appear to be honestly reported, reversal and all. But when the people measuring a therapy's effect are also the people selling it, that's a fact the reader needs before they get to the conclusion, not after. An Assay Grading Its Own Homework PlasticTox is described in the paper as validated by a CLIA-certified reference laboratory. The validation data itself is not disclosed; it's held as proprietary by the company that sells the test. So the entire quantitative backbone of this study rests on an assay whose performance characteristics you're asked to take on faith. This is precisely the kind of thing laboratory medicine exists to prevent. We don't let a diagnostic test dictate a treatment decision until someone outside the company selling it has verified that the test measures what it claims to measure, reliably, across the range of values that matter clinically. An unvalidated assay with undisclosed methods, sitting downstream of a commercial incentive, isn't a minor limitation buried in a discussion section. It's the whole foundation, and it's built on trust rather than evidence. What's Missing Entirely Even if you grant every number in this paper at face value, even if TPE reliably lowers circulating microplastic counts above some threshold, nobody has shown that doing so changes anything for the patient. There is no clinical outcome data here. No symptom scores, no follow-up, no signal that a lower particle count translates to less disease of any kind. The paper answers whether a number can be moved. It does not, and cannot, answer whether moving it helps anyone. Where I Land I don't think the underlying question is silly. Whether microplastics move freely between tissue depots and the bloodstream, whether the blood compartment is a meaningful proxy for total body burden, or just a transit lane, is a real and interesting mechanistic question, and one worth studying properly. If it turns out blood truly is in dynamic equilibrium with tissue stores, apheresis might someday be a legitimate tool for something we don't yet have tools for. But that is not what this paper demonstrates. What it demonstrates is a commercial TPE provider running a therapy already being sold to patients, measured with an assay the company can't independently verify, with no outcome data attached, and a result that reverses at exactly the exposure level most of their patients probably start at. The biology might be worth chasing. The product being sold on the back of it is not the same thing as evidence that it works.

The call comes in from oncology. Their patient — a fifty-something with metastatic melanoma, two months into pembrolizumab — has been confused for three days. Low-grade fever. Can’t tell you the year. Can’t tell you where they are. Infectious workup negative. LP unremarkable. MRI with some FLAIR signal in the mesial temporal lobes. They started high-dose IV methylprednisolone 48 hours ago and the patient isn’t better. Neurology thinks it’s ICI encephalitis. Oncology wants to know if you can do something. You can. Here’s what you need to know. What Is ICI Encephalitis Immune checkpoint inhibitors are monoclonal antibodies. They work by blocking co-inhibitory receptors — CTLA-4, PD-1, PD-L1 — that normally keep T and B cells in check. Releasing those brakes is the whole point: you want the immune system to attack the tumor. The problem is that the same mechanism that kills cancer cells also breaks peripheral self-tolerance, and the collateral damage can affect virtually any organ system. These off-target autoimmune and inflammatory complications are collectively called immune-related adverse events, or irAEs. The nervous system is a particularly vulnerable target. Neurological irAEs occur in roughly 3–12% of patients on ICI therapy, depending on the agent and whether it’s given as monotherapy or in combination. The spectrum is broad: encephalitis, meningitis, Guillain-Barré syndrome, myasthenia gravis, transverse myelitis, cranial neuropathies. ICI-associated encephalitis specifically — inflammation of the brain parenchyma — is rare but can be severe and difficult to treat, particularly once it has failed first-line steroids. Why the Immune System Attacks the Brain The pathophysiology of ICI encephalitis is not a single pathway. It is a convergence of mechanisms, and understanding them matters because the mechanism predicts who will respond to TPE. The most common mechanism is amplification of pre-existing subclinical autoimmunity. Many cancer patients harbor latent B cells or low-titer neural autoantibodies before they ever start ICI therapy — a consequence of the immune system’s exposure to tumor antigens that cross-react with neuronal proteins. These pre-formed autoantibodies are usually held in check by co-inhibitory signaling. When checkpoint blockade removes those inhibitory signals, a subclinical autoimmune process that was already present gets amplified to clinical disease. This is supported by retrospective data showing that anti-Ma2 and anti-acetylcholine receptor antibodies were detectable in pre-treatment sera of patients who later developed ICI-related neurological syndromes. The drug didn’t create the autoimmunity from scratch. It unmasked it. A second mechanism is tumor-driven antigen presentation. Many tumors ectopically express neuronal proteins that are normally sequestered behind the blood-brain barrier. When tumor cells die and release these antigens, dendritic cells take them up and present them to the immune system. Under normal conditions, co-inhibitory signals prevent a full response. Block those signals with a checkpoint inhibitor, and the immune system is primed against neuronal targets shared between the tumor and the brain. The clinical distinction that follows from this is the one that determines your treatment strategy. Encephalitis associated with cell-surface antibodies — anti-NMDAR, anti-LGI1, anti-GABA-B, anti-GAD65, anti-AMPA — is directly antibody-mediated. These antibodies internalize receptors, block synaptic signaling, and activate complement. Remove the antibodies, and the pathogenic process is interrupted. This is why IVIG, TPE, and rituximab work in these cases. Encephalitis associated with intracellular or onconeuronal antibodies — anti-Hu, anti-Ma2, anti-Yo — is driven primarily by a cytotoxic T-cell response. The antibodies are biomarkers, not effectors, and removing them with PLEX is unlikely to change the course of disease. These cases carry substantially worse prognosis — mortality around 23–35% — and respond poorly to antibody-depleting therapies. Why TPE — and Why It’s Different Here When you’re called about a patient with steroid-refractory ICI encephalitis, or other irAE, TPE offers something that other immunosuppression doesn’t: two mechanisms operating simultaneously. The first is the one you’d expect — removing the pathogenic autoantibodies driving the disease process. The second is less obvious and easy to overlook: you are also removing the checkpoint inhibitor itself. Remember that ICIs are monoclonal antibodies, and monoclonal antibodies have long half-lives. Pembrolizumab’s half-life is approximately 27 days. Nivolumab’s is around 27 days as well. Ipilimumab’s is about 14 days. Discontinuing the drug, which is always the first step, does not mean the drug is gone. The patient in your opening scenario stopped pembrolizumab when their symptoms started, but they still have weeks of circulating drug maintaining receptor occupancy on T cells and continuing to drive the inflammatory process injuring their brain. TPE accelerates clearance of the ICI in a way that waiting simply cannot. This dual mechanism — antibody removal plus drug clearance — is what makes TPE uniquely well-suited to the ICI setting. TPE Beyond Encephalitis ICI encephalitis is one indication for TPE. It is not the strongest one. The table below summarizes the irAEs for which PLEX appears in guideline-based management, the role it plays, and key clinical notes. The ICI half-life argument applies across all of them: regardless of the specific irAE, you are treating the immune injury and simultaneously clearing the drug that is sustaining it. Disorder Role of TPE Notes Myasthenia gravis / MG-like syndrome First-line Initiate PLEX or IVIG alongside IV methylprednisolone 1–2 mg/kg/day at grade 3–4; do not wait for steroid failure Guillain-Barré syndrome First-line Start PLEX or IVIG at any grade above mild; steroids added in ICI-related GBS unlike idiopathic GBS Encephalitis Steroid-refractory escalation Add PLEX or IVIG if severe or progressing after 24–48 hours on high-dose methylprednisolone; cell-surface antibody profile predicts better response than intracellular antibody profile Demyelinating disease (optic neuritis, transverse myelitis, ADEM) Steroid-refractory escalation Consider PLEX or IVIG if no response or worsening after 48 hours of high-dose IV methylprednisolone Myocarditis Steroid-refractory escalation Among additional options for hemodynamically unstable patients not improving within 24–48 hours on steroids Triple M syndrome (myocarditis + myositis + MG) First-line for MG component IVIG and/or PLEX specifically indicated for MG-like presentations within the syndrome ICI-induced TTP First-line Standard TTP protocol; single procedure simultaneously removes anti-ADAMTS13 antibody, the ICI itself, and replaces ADAMTS13 from donor plasma What to Tell Oncology When They Call Back to your patient, still confused on day two of methylprednisolone. You are not going to wait for an antibody panel — those are send-outs, and in most centers they aren’t available at all outside a research context. The clinical picture is enough: steroid-refractory ICI encephalitis in a patient who has been off pembrolizumab for days and still isn’t improving. That’s a patient with weeks of circulating drug still driving the process. TPE is a reasonable next step. When oncology asks why TPE and not just more immunosuppression: you are doing two things at once. You are removing whatever antibodies are driving the encephalitis. And you are clearing weeks of circulating pembrolizumab that discontinuation alone cannot touch. That dual mechanism is what makes this worth doing — and what makes it a transfusion medicine problem, not just a neurology one. Checkpoint inhibitors have transformed oncology. They have also created a new category of patient that transfusion medicine is increasingly being asked to manage — patients whose immune systems have been deliberately unleashed and are now doing damage that can’t be walked back with steroids alone. The irAE landscape is broad and still evolving, and the role of TPE within it is broader than most people outside the field realize. Understanding why it works here, and when to reach for it, is increasingly part of what it means to practice transfusion medicine.

There was an attending I worked with as a fellow who had a habit. Patient looks fluid overloaded, hemoglobin is borderline-low-ish, reach for a unit of red cells. The logic, stated out loud more than once: it'll help pull some of that fluid back into the vessels. Oncotic pressure. It made physiologic sense in the moment, the way a lot of things in medicine make sense until you actually look up the numbers. I looked up the numbers. What oncotic pressure actually is Oncotic pressure — colloid osmotic pressure, if you want the precise term — is the pressure exerted by large proteins suspended in plasma that can't easily cross the capillary wall. It's the force that keeps fluid inside your blood vessels instead of leaking into the interstitium. Normal human plasma runs around 25–28 mmHg of oncotic pressure, and the overwhelming majority of that comes from one protein: albumin. Not hemoglobin, not clotting factors, not globulins in any meaningful way. Albumin. This matters because a unit of packed red blood cells is not albumin-rich plasma. It's red cells suspended in a small volume of additive solution with very little protein left in it. Whatever oncotic punch it has isn't coming from the cells themselves — red cells are too large to meaningfully contribute to a colloid osmotic gradient — and there isn't much plasma left to carry albumin along for the ride. The numbers A 2020 study directly measured colloid osmotic pressure across blood products and found packed red cells sit at about 1.9 mmHg. For comparison, fresh frozen plasma measures around 20.1 mmHg, and normal human plasma is roughly 25.4 mmHg. Platelets land somewhere in between, around 7.5 mmHg. Storage didn't change any of this — old units and fresh units had essentially the same low oncotic pressure. The authors' own conclusion is worth sitting with: because RBC oncotic pressure is so low, pulling extra fluid into the vasculature ("third-spacing" fluid into the blood) is an unlikely mechanism behind transfusion-associated circulatory overload, one of the most feared complications of transfusion. In other words, the product my attending reached for to manage fluid overload doesn't have much oncotic pressure to offer. They're just not doing much osmotically, full stop. Okay, but albumin must work, right? This is where it gets more interesting than "RBCs don't work, use albumin instead." Because albumin — the actual oncotic heavyweight, the protein doing 75–80% of the work in normal plasma — doesn't have a clean track record either. The 2026 Surviving Sepsis Campaign guidelines suggest using crystalloids alone over crystalloids with supplemental albumin for fluid resuscitation in adults with sepsis or septic shock, a conditional recommendation based on moderate-certainty evidence. The ALBIOS trial, the largest sepsis-specific study of its kind, found no difference in 28-day mortality between albumin-plus-crystalloid and crystalloid alone. The SAFE trial, comparing albumin to saline across a broad ICU population, found no overall mortality difference either — though subgroup analyses have repeatedly hinted at a possible benefit in septic shock and a signal of harm in traumatic brain injury. Cochrane's own position on albumin has flipped at least once over the decades as new trial data accumulated. The guidelines do carve out two situations where supplemental albumin may still be reasonable: patients who've already received large volumes of crystalloid, and patients with cirrhosis. Outside of those, the oncotic theory and the clinical outcomes data aren't telling the same story. Part of the disconnect may be mechanistic. Albumin's advantage is theoretically largest in a vessel wall that's behaving normally. In sepsis and other inflammatory states — exactly the conditions where clinicians are most tempted to reach for it — capillary permeability increases, and infused albumin can leak into the interstitium right along with crystalloid. Once albumin is outside the vessel, it pulls fluid outside the vessel with it, paradoxically worsening fluid overload. Sitting with the gap So here's where I land, and I want to be honest that it's not a clean place to land: neither RBCs nor albumin reliably produce the specific physiologic outcome — durable intravascular fluid retention — that you would predict. RBCs because there's barely any oncotic pressure to speak of. Albumin because the theoretical advantage gets diluted by capillary leak in exactly the patients where it's most often considered. I don't think this means "never give albumin" or "never transfuse RBCs in fluid overload." There may be other legitimate reasons to transfuse a fluid-overloaded patient — symptomatic anemia doesn't go away just because someone's also volume overloaded, and the clinical picture is rarely just one variable. What I think this does mean is that "it'll help pull fluid back in" is doing a lot of work that the data doesn't actually support, for either product. The harder version of this "It physiologically makes sense" and "it has been measured to do that in patients" are two different claims, and a fair amount of practice in medicine quietly substitutes the first for the second. Oncotic pressure is real, measurable, and important. It's also not a license to assume that giving a product with theoretically favorable properties produces the clinical effect we're hoping for. Sometimes the most rigorous thing you can do with a comfortable physiologic story is go check whether it survived contact with a colloid osmometer. References Klanderman RB, et al. Colloid osmotic pressure of contemporary and novel transfusion products. Vox Sanguinis. 2020.

A patient calls the clinic the morning of their appointment. Their ride canceled. Again. The scheduler offers to rebook, but the patient hesitates — they've already canceled twice this month for the same reason, and they're starting to wonder if the clinic thinks they just don't want to come in. They do. They just can't get there. I've heard versions of this story enough times recently that it stopped feeling like a string of coincidences and started feeling like a pattern. Transport companies are declining Medicaid and Medicare rides because the reimbursement doesn't cover the cost of fuel to get there. No-shows and cancellations are climbing. And in a separate but oddly parallel thread, research coordinators are reporting that study participants — people who once reliably showed up for their visits — are skipping appointments because the incentive payment no longer covers what it costs to drive there. These are two different systems, two different funding mechanisms, two different sets of patients. But they're failing for the same underlying reason, and I don't think that's a coincidence. How a flat rate breaks under a variable cost Non-emergency medical transportation, or NEMT, is supposed to be the safety net that gets Medicaid and Medicare beneficiaries to dialysis, infusion, oncology follow-up, and the dozens of other appointments that can't happen by telehealth. The way these trips are usually priced is a base rate plus a per-mile mileage fee, and that mileage fee is explicitly built to reflect local fuel prices, vehicle maintenance, and regional economic conditions. Reimbursement rates themselves vary enormously by state — the same wheelchair-accessible trip might pay around $100 in one state and roughly a third of that in another, because federal law requires states to provide NEMT but leaves the actual payment rate entirely up to them. That structure works fine as long as the underlying cost of driving stays roughly where it was when the rate was set. It does not work when fuel prices climb faster than the rate gets revised. A transport company running on Medicaid mileage reimbursement doesn't have the option of just absorbing the loss trip after trip — they stop taking the trips. Which is, anecdotally, exactly what's happening. The data we already had Here's the part that surprised me a little: we didn't need a fuel crisis to know transportation barriers cause missed appointments. That literature already exists, and it's not small. A frequently cited estimate puts the number at roughly 5.8 million Americans missing or delaying medical care annually because of transportation barriers, concentrated in rural and underserved urban areas where transportation options are already limited. In one study of caregivers in Houston, an inability to find a ride caused at least one missed appointment in a quarter of the sample. A systematic review and meta-analysis of interventions aimed at exactly this problem — vans, bus vouchers, rideshare — found they meaningfully reduced missed appointments, though the evidence on whether that translated into better health outcomes or lower costs was too thin to say for sure. So the mechanism by which "can't get a ride" becomes "missed dialysis session" was already well established. What's new isn't the mechanism. It's the scale and speed at which fuel prices are stressing a system that was already running close to the edge. The same problem, wearing a different badge The research side of this is structurally different but rhymes uncomfortably well. Clinical trial and study compensation has its own literature on travel reimbursement, and it's clear on one point: covering travel costs isn't a perk, it's often the thing standing between "this person can participate" and "this person can't afford to." One review of payment practices noted that travel costs remain one of the most significant barriers to clinical trial participation, particularly for low-income participants. Separately, researchers studying recruitment and retention have argued that travel reimbursement is an appropriate and valuable incentive precisely because, without it, participation becomes a luxury good — available to people who can absorb the cost of getting there, and closed to everyone else. If incentive payments were calibrated to cover a $15 round trip in gas and now the actual cost is closer to $25, that calibration has quietly become a barrier, even though the dollar amount on paper hasn't changed. The people most likely to drop out under those conditions are, predictably, the people for whom that gap matters most — which is its own quiet threat to the diversity and generalizability of the data we're collecting. What I can't tell you yet I want to be honest about the limits of what I'm describing. There is, as far as I can find, no published literature yet on this specific moment — on fuel prices rising fast enough to push NEMT providers out of Medicaid and Medicare contracts, or on research incentive payments failing to keep pace with gas prices in real time. What I have is a well-documented mechanism (transportation barriers cause missed appointments and lower trial retention) colliding with an acute, recent stressor (fuel costs outpacing reimbursement) that hasn't been studied yet because it's still happening. It would be tidier to end this with a clear causal claim and a clean policy fix. I don't think I'm entitled to either yet. What I can say is that two systems I don't normally think about together — clinical transportation logistics and research recruitment economics — are both showing the same symptom right now, and that symptom is patients and participants disappearing from the schedule not because they don't want to be there, but because the math of getting there no longer works. A structural irony, if you're looking for one The patients most likely to need frequent transportation-dependent care — dialysis, transfusion, infusion therapy, complex follow-up — are, by definition, the ones who can least afford for this particular gap to widen. We built a system where access to care depends on a per-mile rate someone set years ago, in a different fuel market, and we're now finding out what happens when that assumption quietly stops holding.

In 2008, an FDA advisory panel sat down with a meta-analysis that pooled thirteen randomized trials of cell-free hemoglobin-based oxygen carriers — HBOCs, for short — and found that, as a class, these products increased the risk of myocardial infarction and death compared to controls. Within the year, the FDA had effectively frozen HBOC development in the United States. Almost two decades later, the freeze hasn’t really lifted. One of the products caught in it, Hemopure, has spent that entire time legally available in South Africa, used there since 2001 for acute surgical anemia, with no comparable reckoning. That gap is the interesting part. Not whether Hemopure works — it does, in the narrow sense of carrying oxygen — but why a product can be standard of care in Johannesburg and investigational-only, accessible solely through expanded access protocols, in Boston. The Pitch Hemopure (HBOC-201) is purified, glutaraldehyde-polymerized bovine hemoglobin, suspended in a balanced electrolyte solution and packaged in a 250 mL bag. It solves, on paper, two of transfusion medicine’s oldest structural problems at once. First, compatibility: there’s no antigen to react to, so no type and screen, no crossmatch, no antibody workup — a feature that matters enormously for a patient with a complex alloantibody history, or a Jehovah’s Witness declining allogeneic blood, or a combat medic with no time and no lab. Second, supply: it’s shelf-stable at room temperature for years, not the 42 days we get out of refrigerated red cells. No cold chain, no expiration anxiety, no donor recruitment problem. It is, in other words, exactly the product blood banking has wanted since the first synthetic oxygen carrier was proposed. Which is part of why its failure to gain US approval stings more than a typical drug rejection — this isn’t a marginal improvement on an existing therapy. It’s a different category of solution to a problem we still haven’t solved. What the Meta-Analysis Actually Said The 2008 Natanson analysis, published in JAMA, didn’t study Hemopure alone. It pooled data across five distinct molecules — HemAssist, PolyHeme, Hemolink, Hemopure, and Hemospan — spanning surgical, trauma, and stroke populations treated between 1980 and 2008. The conclusion was stark: roughly a 30% increase in risk of death and nearly a threefold increase in risk of myocardial infarction across the pooled trials. The FDA responded by putting HBOC research as a class on clinical hold, and pharmaceutical interest in the space mostly evaporated. The proposed mechanism made biological sense and still does: free hemoglobin outside the protective confines of a red cell membrane scavenges nitric oxide, the molecule responsible for vasodilation. Scavenge enough of it and you get vasoconstriction, hypertension, and — plausibly — myocardial ischemia. This isn’t a manufacturing defect specific to one company. It’s closer to a property of cell-free hemoglobin itself, which is a much harder problem to engineer around. The Harder Question Here’s where I think the story gets genuinely uncomfortable, and where I have a hard time being charitable to the paper that started all of it. Natanson and colleagues pooled thirteen trials of five chemically distinct molecules — different polymerization strategies, different patient populations, different routes and doses, trauma and elective surgery and stroke trials run across nearly three decades — into a single composite risk estimate, and reported finding no significant statistical heterogeneity across that grab-bag. I find that more suspicious than reassuring. Getting a clean, homogeneous-looking signal out of five drugs that don’t share a structure, in populations that don’t share a baseline ischemic risk, is exactly the kind of result that should prompt a second look at the methodology rather than a press release. Several independent groups thought so too: JAMA ran six separate rebuttal letters in the same issue — from South African clinicians with the largest real-world experience with Hemopure, from the manufacturers, from trauma surgeons, from bioethicists — which is not a normal amount of pushback for one meta-analysis to generate. Natanson’s own paper acknowledged that the authors had struggled to obtain complete trial data directly from the companies, meaning the headline number was built partly on data the authors themselves described as incomplete. It also doesn’t help that the senior author, Sidney Wolfe of Public Citizen’s Health Research Group, had already petitioned the FDA over HBOC trial safety back in 2006 — two years before he co-authored the analysis that became the FDA’s rationale for freezing the entire class. None of that automatically makes the conclusion wrong. But a paper with this many independent critics, this much acknowledged missing data, and an author who’d staked out the answer in advance is not the kind of evidence I’d want sitting alone at the foundation of a two-decade regulatory freeze — and yet here we are, two decades later, and it still is. And then there’s the South Africa and Russia question, which nobody seems eager to sit with for very long. If the safety signal were straightforwardly damning, you’d expect those approvals to have been revisited over twenty-plus years of real-world use. They haven’t been. Either the signal doesn’t replicate cleanly outside the specific trial populations that generated it, or post-marketing surveillance in those countries simply isn’t rigorous enough to have caught it — and I genuinely don’t know which of those is true. Both possibilities should make a transfusion medicine physician uneasy, just in different directions. Meanwhile, expanded access use in the US has quietly continued for patients with life-threatening anemia and no other option — mostly Jehovah’s Witnesses and patients with antibody profiles that make compatible blood functionally unobtainable. Case series from these programs report real patients surviving severe anemia they likely wouldn’t have survived otherwise, alongside the same cardiovascular signal the trials raised. The regulatory caution and the individual patient calculus are not measuring the same thing, and I don’t think they’re supposed to converge. A population-level hold protecting against a class-wide signal can be correct and still be the wrong answer for the specific patient in front of you with no other option. Sitting with that tension honestly is harder than resolving it in either direction. Where It Sits Now Hemopure remains investigational in the US, available only through expanded access or clinical trial. HbO2 Therapeutics, the company that now holds the product after Biopure’s bankruptcy and a subsequent ownership chain, has kept it alive primarily through that compassionate-use pathway and continued approval in South Africa and Russia. The broader HBOC field never really recovered momentum after 2008; most of the other products named in the Natanson analysis are gone entirely. Hemopure is something closer to a survivor than a success — still infused, still studied in scattered case reports, still without a clear path to a US indication. There’s a newer thread worth watching: small case literature on HBOC-201 for ischemic rescue in cardiology and vascular contexts, distinct from its original blood-substitute framing. Whether that becomes a real niche or stays anecdotal is an open question, and I’m not going to pretend I know which. I don’t think this is a story with a villain. The FDA did what regulatory agencies are supposed to do when a meta-analysis raises a mortality signal across a drug class. But twenty years on, with the same product still quietly saving the occasional patient who has no other option, and still in routine use on two other continents, I find myself less sure than I’d like to be about whether the caution and the evidence are still pointing in the same direction — or whether we’re applying a 2008 verdict to a 2026 question.

The system is collapsing. Before we try to save it, we should ask whether it was working. Something Has Changed Something has changed in academic publishing. Papers I submit take longer to get reviewed than they used to. Desk rejections — the kind where a paper doesn’t make it out to reviewers at all — feel more common. When a review does come back, it sometimes arrives months after submission, accompanied by an apology from an editor who clearly struggled to find anyone willing to assess the manuscript. I’ve wondered if I’m imagining it, or if my experience is just narrowly my own. It isn’t. The Infrastructure Is Fraying Simberloff and colleagues recently published 21 years of editorial data from Biological Invasions — a granular, longitudinal dataset that makes the pattern hard to argue with. In 2003, more than 60% of invited reviewers accepted. By 2023, that number had fallen to just below 40%. Decline rates rose to match. The lines have now converged: for every scientist who says yes, one says no. If the trend holds, declines will soon outpace acceptances. This is one journal, one field. But a 2018 Publons survey found something consistent across all scientific disciplines: 10% of reviewers complete more than half of all reviews. The system is not failing uniformly. It is being held together by a small, overloaded minority while everyone else declines — and, increasingly, doesn’t bother explaining why. In the Biological Invasions data, the most common reason given for declining is being too busy, a response that has grown more frequent over time. Lack of expertise is also frequently cited. But roughly half of all decliners give no reason at all. There are no consequences for saying no, so scientists have stopped feeling the need to justify it. But Was It Ever Working? Before we treat this as an unambiguous crisis, it’s worth asking what exactly we’re losing. Peer review has long been treated as the quality-control mechanism of science — the filter that keeps bad research out of the record. That assumption deserves scrutiny. The psychologist Adam Mastroianni has written compellingly about peer review as a failed experiment. The evidence he marshals is uncomfortable. Studies in which researchers deliberately inserted major errors into manuscripts — things like misrepresented study designs, unsupported conclusions, obvious discrepancies between data and graphs — found that reviewers caught somewhere between 25 and 30% of them. Not 25 to 30% of minor quibbles. Major methodological flaws. Most of what reviewers are supposed to catch, they miss. The fraud data tell the same story. If peer review were functioning as a rigorous filter, we would hear about fraud attempts stopped at the gate. We don’t. Almost every high-profile case of scientific fraud begins with a paper that passed review and was published. The detection comes later — from a lab member, a methodologist, someone on the internet who noticed something odd about the error bars. Review did not catch it. Post-publication scrutiny did. None of this means peer review does nothing. It probably catches some errors, improves some papers, and deters some bad actors who would otherwise have no barriers at all. But the gap between what peer review promises and what it delivers is substantial. We have been running on faith more than evidence. The Bargain We Made The deeper problem is what got built on top of peer review’s assumed reliability. Hiring committees treat publication in peer-reviewed journals as a proxy for scientific quality. Grant agencies use it as evidence of track record. Clinicians — and I count myself here — use peer-reviewed literature to make decisions about patient care. The peer-reviewed label became a kind of certification, and institutions downstream of the scientific record built their practices around it. That certification was always shakier than it looked. But the response, broadly, has been to defend peer review rather than examine it — to argue that more of it, or better-resourced versions of it, would fix the problem. The collapse now underway is forcing a different question: not how do we sustain peer review, but what do we actually need from it, and is there a better way to get there. Why Nothing Will Change Here is the detail from the Simberloff paper that has stayed with me. The editors-in-chief of Biological Invasions — the people running the journal, watching decline rates climb year after year, doing the actual work of recruiting reviewers into an increasingly reluctant pool — asked Springer Nature, their own publisher, for reviewer incentives. They asked multiple times. Springer Nature declined. This is not surprising. It is clarifying. Springer Nature collects subscription fees, article processing charges, and the commercial value of a prestigious catalog, all sustained by the unpaid labor of reviewers and the prestige conferred by the peer-review label. There is no version of that business model that benefits from fundamental reform. The current system, however dysfunctional, is profitable. Incentives to change it would have to come from somewhere else. This is also part of a larger pattern. Park and colleagues’ 2023 analysis of 45 million papers spanning six decades found a steady decline in disruptive science — work that challenges existing frameworks rather than incrementally extending them. The same incentive structure that rewards volume over depth is now degrading the mechanism that was supposed to ensure quality. More submissions, fewer willing reviewers, and the institutions profiting from the system declining to invest in its sustainability. We Need a New Model There are alternatives being tried. Preprint servers like bioRxiv and medRxiv allow rapid dissemination before formal review, with post-publication scrutiny doing some of the work that pre-publication review was supposed to do. Open peer review, where reviewer identities and comments are made public, attempts to introduce accountability into a process that currently operates without it. Some journals are experimenting with paying reviewers. These are not nothing. But none of them have yet accumulated the institutional weight that peer-reviewed publication carries. Hiring committees still count papers. Grant agencies still look at journals. Clinicians still defer to the peer-reviewed label, even knowing what we know about its limitations. The alternative models exist at the margins while the incumbent system, imperfect and increasingly unsustainable, holds the center. I don’t know what the right model looks like. I don’t think anyone does with confidence. What I do know is that we need one, that the timeline is shorter than it probably feels, and that the people with the resources and infrastructure to build it have spent decades demonstrating they have no intention of doing so. That is the peer review bargain in 2025: a system that over-promised on quality, under-delivered on rigor, is now running out of the volunteers who kept it going, and has no obvious succession plan. Referenced works: Simberloff D et al. (2025). Quantifying reviewer declines in scientific publishing: twenty-one years of data from Biological Invasions 2002–2024. Biological Invasions, 27, 223. https://doi.org/10.1007/s10530-025-03679-1 Mastroianni A. (2022). The rise and fall of peer review. Experimental History. https://www.experimental-history.com/p/the-rise-and-fall-of-peer-review Park M et al. (2023). Papers and patents are becoming less disruptive over time. Nature, 613, 138–144. https://doi.org/10.1038/s41586-022-05543-x

It’s two in the morning. Your pager goes off. A nurse tells you her patient spiked a fever — 38.4°C, up 1.2 degrees from baseline — about two hours into a unit of packed red cells. She stopped the transfusion and is waiting for your call. You work it up. DAT negative. Plasma clear. No hemoglobinuria. No respiratory distress. No hypotension. The patient’s mildly uncomfortable but gets better with acetaminophen. In the morning you write it up: febrile non-hemolytic transfusion reaction, FNHTR, imputability definite. Classic presentation. Before January 2026, that case went into the National Healthcare Safety Network Hemovigilance Module as a reportable adverse reaction. It became one data point in a national count of how often this happens, in which patients, with which products. After January 2026, it goes nowhere. You file it in your own system, call it whatever you call it, and move on. That change is the story I want to tell. What Changed The NHSN Hemovigilance Module has been the national platform for transfusion safety surveillance in U.S. hospitals since 2009. For most of its life, it asked participating facilities to report a broad taxonomy of adverse reactions — twelve defined reaction types across twenty separate forms — classified by case definition, severity, and imputability. Reactions that were possibly, probably, or definitely related to a transfusion were required. Every FNHTR. Every allergic reaction above the minor threshold. Every delayed hemolytic. Every hypotensive reaction. The idea was to capture the full landscape of transfusion-associated harm. Version 3.0, released in January 2026, makes a dramatic cut. Required reporting now covers exactly four reactions: transfusion-associated circulatory overload (TACO), transfusion-related acute lung injury (TRALI), acute hemolytic transfusion reaction (AHTR), and transfusion-transmitted infections (TTI). Everything else — FNHTR, delayed hemolytic, delayed serologic, allergic, hypotensive, transfusion-associated dyspnea, post-transfusion purpura, transfusion-associated graft versus host disease — is now classified as “Other.” The “Other” category is optional. And the CDC has stated explicitly that “Other” data will not be used to calculate rates. Twenty forms became four. Twelve defined reaction types became four, plus a catch-all. What the New Module Gets Right The case for simplification is real. One of the quiet problems with the old module was inconsistent participation. Not every institution had the infrastructure to report reliably. The imputability framework — which required classifying each reaction as definitely, probably, possibly, doubtfully, or not related to the transfusion — was applied unevenly across hospitals, with significant variability in how individual blood banks interpreted and recorded those categories. A national database is only as good as the data going into it, and data entered inconsistently is a form of noise. Fewer required forms means lower burden, and lower burden means better compliance. If the goal is accurate national surveillance of the most dangerous transfusion reactions, it makes sense to focus on the reactions most likely to cause serious harm or death. TACO, TRALI, AHTR, and TTI represent the sharp end of the risk spectrum. They are the reactions you lose patients to. A TTI Rapid Alert form that triggers within 72 hours — a new feature in v3.0 — is a genuinely useful public health tool for catching emerging pathogens in the blood supply before they spread. The new module also adds a TTI Investigation Form with a structured pathway for coordinating between hospitals, health departments, and the CDC. That’s a meaningful improvement in how we respond to the reactions that matter most urgently. What We Might Be Giving Up Here is where I want to slow down. The first loss is data. FNHTR is the most common transfusion reaction we see. Allergic reactions are a close second. Delayed hemolytic transfusion reactions, particularly in patients with sickle cell disease, can be life-threatening. These reactions are now optional to report and will no longer appear in national rate calculations. If you want to know how often FNHTR happens per unit transfused in the United States, or whether that rate is changing, you will not be able to answer that question from NHSN data going forward. The baseline we’ve been building since 2009 is effectively being abandoned for these reaction types. The second loss is resolution. Collapsing eight defined reaction types into “Other” doesn’t make those reactions disappear — it just makes them indistinguishable from one another in the national record. A hypotensive reaction and a delayed serologic reaction both go into the same optional bucket. The third loss is perhaps the most underappreciated. For fifteen years, the NHSN Hemovigilance Module provided something that the field rarely talks about explicitly: a shared vocabulary. The case definitions — FNHTR requires fever ≥ 38°C with a change of at least 1°C from baseline, or chills, within four hours of transfusion cessation; DHTR requires a positive DAT between 24 hours and 28 days with serologic evidence and inadequate hemoglobin rise — were the language everyone agreed to speak. The module’s own protocol disclaimed clinical use of these definitions, and yet every transfusion medicine fellow learned them. Every blood bank used them. Every paper in this field cited them. Those definitions still exist in Section 6 of the new protocol, archived for reference. But they are no longer the required framework for national reporting. Without that institutional anchor, definitional drift will come. Not immediately — the field’s memory is long — but over a decade, as trainees learn from attendings who learned from a protocol that no longer exists in the same form, variability will creep in between institutions, between publications, between how we talk to each other about what a reaction even is. The Honest Landing I don’t think this change is obviously wrong. The logic behind it is defensible, and the improvements to TTI surveillance are real. What I can’t tell you is whether the tradeoffs will be worth it. That answer will take years to emerge, and by the time we know, we will have already lost the data we chose not to collect. That’s the thing about surveillance systems. The cost of narrowing them is invisible at first. You don’t see the data you’re not gathering. You don’t miss the baseline you’re no longer building. The gap only becomes visible later, when someone asks a question about FNHTR rates in 2030 and realizes the answer stopped being tracked in 2026. For now, my FNHTR gets documented in our local system, classified with whatever terminology we happen to use, and counted in no national total. Whether that’s fine — whether the simplification is worth the resolution we gave up — is a question I’m genuinely not able to answer yet. I’m curious whether others in the field see it differently.

The pager goes off. The message reads: “Bloodless surgery consult — patient refusing blood products.” If you are a transfusion medicine fellow and this is your first one, you probably spend a moment staring at your pager wondering exactly what you are supposed to do with that information. You show up, introduce yourself, and are handed a form. It is several pages long. At the top, in clear block letters: WHOLE BLOOD COMPONENTS. Below that, a list of products — red blood cells, platelets, plasma — each followed by two checkboxes. Accept. Reject. It seems simple enough. Then you keep reading. By the time you reach plasma protein fractions, recombinant clotting factors, and thrombopoietin mimetics, you realize this is not a simple form. It is a document that asks a person to think, in advance and in detail, about exactly how much of their own blood — and everyone else’s — they are willing to accept back into their body under duress. The checkboxes are tidy. The clinical reality underneath them is not. Why This Consult Exists The most common reason you will encounter a bloodless surgery consult is a patient who is a Jehovah’s Witness. Members of this faith generally decline transfusion of whole blood and its four primary components — red blood cells, white blood cells, platelets, and plasma — based on a religious interpretation of scriptural passages prohibiting the “taking in” of blood. But the boundaries of that refusal are personal, not prescribed. Individual Jehovah’s Witnesses vary significantly in what they will and will not accept, which is precisely why the form exists and why the consult matters. Not every patient requesting bloodless or transfusion-free care is a Jehovah’s Witness. Some patients have religious objections that are less formalized. Others have philosophical objections to allogeneic blood, concerns about transfusion-transmitted infections, or simply a strong preference to avoid a product they view as high-risk. The label “bloodless surgery” is something of a misnomer — the goal is not zero blood, but zero allogeneic blood. Whether that is achievable depends on the clinical situation, the alternatives available, and what the patient has actually agreed to. The form is the tool that documents that agreement. The conversation is the actual work. The Form, Decoded Walk through the major product categories and the clinical stakes become clearer. Whole blood components — red cells, platelets, plasma, white cells — are the straightforward part. Most patients who have thought carefully about this have already made their decision about these products before you walk in the room. These are the checkboxes they came prepared for. Plasma fractions are where things get philosophically interesting. Albumin is derived from pooled human plasma, fractionated, and heat-treated. Cryoprecipitate is thawed plasma precipitate, rich in fibrinogen and factor VIII. Fresh frozen plasma is essentially unfractionated. A patient might accept albumin but decline FFP, not because they are being inconsistent, but because fractionation changes the product enough to matter to them, even if it does not particularly change the clinical calculus for you. This is not a contradiction you are there to resolve. It is a distinction you are there to understand and document. Autologous techniques — cell saver, acute normovolemic hemodilution, apheresis, dialysis — occupy a fascinating middle ground. Many patients who decline allogeneic blood are entirely comfortable with their own blood being collected, processed through a machine, and returned to them, as long as the circuit remains closed and continuous. The blood never “leaves” them in any meaningful sense. Practically, this means cell saver is often on the table even when packed red blood cells are not, and that distinction matters enormously in a surgical or hemorrhage scenario. Erythropoiesis-stimulating agents, colony-stimulating factors, and thrombopoietin mimetics round out the list. These are pharmacologic scaffolds — tools to build up what the patient has before a major procedure, or to support recovery after one. Some formulations contain albumin as a stabilizer. For some patients, that matters. For others, it does not. You need to know which. The Grey Area Nobody Warns You About: Plasma-Derived Clotting Factors Here is something the form does not make obvious, and that fellows often do not realize until they are standing at the bedside: several of the products in the “clotting factors” section are derived from pooled human plasma. Kcentra — the four-factor prothrombin complex concentrate most of us reach for in warfarin reversal or urgent coagulopathy — is plasma-derived. So is Riastap, the fibrinogen concentrate. Humate-P, which contains both factor VIII and von Willebrand factor, is plasma-derived. These are not recombinant products engineered in a lab. They are fractionated from pooled donor plasma, processed and pathogen-reduced, but fundamentally the same source material as fresh frozen plasma. The processing is different. The origin is not. A brief detour into hemophilia is useful here, because the recombinant versus plasma-derived distinction has a history that most fellows outside of hematology do not fully appreciate. For most of the twentieth century, factor VIII and factor IX concentrates used to treat hemophilia A and B were plasma-derived — pooled from thousands of donors, with all the viral risk that entailed. The consequences in the 1980s were devastating: contaminated plasma-derived concentrates transmitted HIV and hepatitis C to a substantial portion of the hemophilia population before adequate screening and viral inactivation methods existed. That disaster drove the development of recombinant factor products, which began reaching the market in the early 1990s. Today, recombinant factor VIII and factor IX concentrates — including extended half-life versions — are the standard of care for hemophilia in high-income settings. Plasma-derived equivalents still exist and are still used, particularly where recombinant products are less accessible, and in conditions like von Willebrand disease where a plasma-derived product containing both factor VIII and vWF is sometimes preferred. But the field has largely moved on. The relevance for bloodless surgery is this: the products you are most likely to reach for in an acute coagulopathy — Kcentra, Riastap — do not yet have widely available recombinant equivalents. A recombinant fibrinogen concentrate exists in development but is not in routine clinical use. So unlike hemophilia care, which has largely transitioned away from plasma-derived products, the hemostatic toolkit for your typical bleeding surgical patient is still substantially plasma-derived. That gap matters when your patient has declined plasma. Where recombinant options do exist, they matter a great deal. Recombinant factor VIIa (NovoSeven) is produced in baby hamster kidney cells — no human plasma involved. Recombinant factor VIII and factor IX are similarly plasma-free. For a patient whose objection extends to all human blood fractions, these products may be acceptable where plasma-derived concentrates are not. The reverse can also be true: some patients are comfortable with highly processed plasma fractions but draw the line at whole plasma or red cells. You cannot predict which way a given patient will land. The form gives you a framework. The conversation gives you the actual answer. This is one of the more uncomfortable aspects of bloodless surgery medicine: the fellow’s job is not just to document preferences, but to ensure those preferences are genuinely informed. That means being willing to say, politely and clearly, “I want to make sure you know that this product comes from human plasma — is that still acceptable to you?” Most patients appreciate it. Some are surprised. Occasionally, it changes their answer. All of those outcomes are better than the alternative. When the Checkboxes Run Out The form creates legal clarity. It does not always create clinical clarity. Consider a patient who has accepted cell saver but declined cryoprecipitate. Intraoperatively, they develop a coagulopathy. The surgeons look at you. The anesthesiologist looks at you. The patient is not in a position to revisit their checklist. You are not there to override their documented wishes — you are there to help the team understand what options remain, and what their limits are. In practice, this means knowing your alternatives well enough to deploy them quickly. Can you correct a fibrinogen deficit with a fibrinogen concentrate the patient has accepted? What is the hemostatic ceiling of topical procoagulants like fibrin sealants? Is the surgical team using electrocautery aggressively enough? Is there an interventional radiology option? The transfusion medicine fellow in the bloodless surgery consult is not just a documentarian. You are a consultant in the truest sense — someone whose job is to expand the team’s range of options, not just to manage their expectations. And then there are the cases where the options run out. Where the patient is bleeding and the only thing that would reliably help is a product they have refused. You learn to sit with that. You learn that informed refusal is not a failure of medicine. You learn that the consult you did beforehand — the one where you made sure the patient understood exactly what they were declining, and why, and what the alternatives were — was the most important one. What These Consults Teach You Bloodless surgery consults are a masterclass in what blood products actually do. Because you cannot default to transfusion, you have to explain — to the patient, to the team, and to yourself — exactly what each product is for, what happens physiologically without it, and what can plausibly substitute. You will leave your first few of these consults knowing your coagulation cascade better than you did going in. That is an underappreciated upside. You also learn something about the nature of consent itself. Most informed consent in medicine is procedural: sign here, you understand the risks. Bloodless surgery consent is longitudinal. It happens before the procedure, often well before, and it asks the patient to project themselves into scenarios they cannot fully anticipate. It demands that you, as the consultant, be honest about uncertainty — about what the surgery might require, about which alternatives are genuinely equivalent and which are merely adjacent. Accept or Reject The form implies a binary. Accept. Reject. Medicine is almost never that clean. The most useful thing I can tell a fellow going into their first bloodless surgery consult is this: the form is not the point. The point is the conversation that produces it — the one where you find out what the patient actually believes, what they actually understand, and what they are actually willing to accept when the stakes become real. The checkboxes are documentation. The consult is medicine. And if you leave that room feeling like you understood it completely, you probably missed something.