Low Blood Volume in ME, Part II
Rheology, Morphology and the Third Space
Copyright 2025 Hillary Johnson. All Rights Reserved.
In the late 1990s, retired pediatrician David Bell was increasingly impressed by symptoms of severe low blood volume in ME patients and bewildered that the larger ME research community seemed uninterested. Bell considered low blood volume a critical piece of the ME puzzle. He noted that low blood volume was particularly dramatic in women. A subportion of female patients in his own admittedly small studies had blood volumes so low they fell into a subset of ME patients with half or even less than half of normal. They were in Grade IV shock, in other words, the deadliest category.
“Women’s blood loss was twice as severe as men’s,” Bell told me.
Men’s blood volume deficits, if they had them, seemed unrelated to the severity of their disease.
“I’ve been very much—very much frustrated,” Bell told me when we first discussed the phenomenon in 2018 at his farmhouse near Lake Ontario in upstate New York. “There is no question that the blood volume is decreased about fifty percent in many patients. I think it’s important. If you have a stroke and it cuts off a certain amount of blood to the brain, you have tremendous symptoms. But nobody has ever looked at [the impact of blood loss on the brain] in this disease. There is so much that is unexplained in this illness that is related to the basics,” Bell adds. “We ought to start there.”
Assuming low blood volume is a feature of ME, a question arises: what is causing blood loss? Also, where is the blood going?
One hypothesis Bell proposes is the leakage of blood through patients’ capillaries into the interstitial or “third space” between cells. The latter phrase is sometimes employed as a verb: “third spacing.” “Interstitial” refers to areas outside the vascular or circulatory system where blood and fluids may collect between cells, organs and tissues. Bell notes such leaks, or third spacing, into the interstitial spaces might be occurring because a virus is infecting the capillaries, the smallest blood vessels in the body. Bell adds that while scientists have yet to identify a causative pathogen in ME, “it’s probable” that there is one.
Discoveries in the 1980s that ME patients’ red blood cells are misshapen offer another clue. These findings seemed important at the time, but investigators have made limited progress in expanding this line of research.
In 1986, Australian scientist Leslie Simpson, who studied the properties of blood cells and blood flow in multiple sclerosis and other diseases, published a pilot study about strangely shaped red blood cells in ME. Simpson was researcher at the University of Adelaide in South Australia. His expertise was in “hemorheology.” Medicine defines blood rheology as “flow properties” of blood and its components, like plasma and red cells.
Simpson was intrigued by the disease because he believed that its symptoms were suggestive of impaired microcirculation. The implications were dire. Red cells carry oxygen throughout the body; impaired blood flow interferes with oxygen delivery to the brain and other organs, potentially causing cell death.
In 1986, Simpson confirmed his suspicions, reporting that “(The) acute phase of (ME) is associated with changes in blood rheology which could impair microcirculatory blood flow.”
Simpson observed that a proportion of ME red blood cells were “cup shaped.” In healthy people, red blood cells are “disk-shaped.”
A precedent for Simpson’s hypothesis is sickle cell anemia. In that disease red blood cells develop a sickled or crescent appearance. The sickle shape impedes red cells from passing through small vessels.
Three years later, in 1989, Simpson revisited the topic, publishing the results of a second study comparing the blood of ME patients, multiple sclerosis patients and healthy people. Simpson titled his paper Nondiscocytic Erythrocytes in Myalgic Encephalomyelitis. This time, Simpson found that ME sufferers had the most abundant numbers of deformed red blood cells among the three groups. Once again, the cells had a cup-shape rather than a disk-shape.
Simpson was so impressed that he proposed the presence of misshapen cells might be diagnostic of ME.
“Samples from subjects with myalgic encephalomyelitis had the lowest percentages of normal red cells and the highest incidence of cup forms,” Simpson wrote. “Quantitative analysis of red cell shape may assist in the diagnosis of myalgic encephalomyelitis.”
New Zealand investigator Tapendra Mohan Mukherjee published his own paper about red blood cells in ME patients in 1987, in between Simpson’s first and second papers on the subject. Mukherjee, who died in 2001, was head of electron microscopy at the University of Otago in New Zealand in 1965. He joined the electron microscopy unit at the Institute of Medical and Veterinary Science in Adelaide in 1969.
Like Simpson, Mukherjee reported that red blood cells in ME patients were misshapen and proposed that the abnormal cells were unlikely to pass through capillaries.
Mukherjee felt passionate about his finding. Throughout his life he lobbied—unsuccessfully—for equipment and funding for ME research in South Australia in order to pursue investigation of the disease.
Morphological alteration of red blood cells is hardly exclusive to ME. Sickle cell anemia is an obvious example of the phenomenon. Since altered red blood cell morphology may exist in other diseases, comparative studies, like Leslie Simpson’s 1989 comparison of ME and MS, seem justified in order to determine the severity of the problem in ME, not merely its existence.
Sheerly coincidentally, as I was researching this topic in 2018, I noticed a new paper on the topic of red blood cell deformities in “Gulf War Illness.” The title: “Abnormal rheological properties of red blood cells as a potential marker of Gulf War Illness: A preliminary study.”
In their paper, the investigators described the red blood cells as “deformed” in each of seventeen patients with Gulf War Illness. The ten healthy controls were negative for this finding.
“…[C]hronic symptoms that include fatigue, pain and cognitive impairment,” marked the disease, they wrote. Their conclusion? “This symptom cluster may be the consequence of impaired tissue oxygen delivery due to red blood cell dysfunction.”
In 2019, Ron Davis, the Stanford biochemist and geneticist, published a paper in which he suggested ME red blood cells were “stiffer” than healthy cells and for that reason might impair circulation.
Davis wrote—optimistically—that the finding “promises to be a novel first-pass diagnostic test.”
An Aside: The Politics of Diagnostics
In 1988, one year after Mukherjee published his observations, the CDC published it’s “working case definition” of ME and introduced its new name for the disease, “chronic fatigue syndrome,” in the Annals of Internal Medicine. The agency claimed the disease was “characterized primarily by fatigue,” a disastrous statement that has skewed the direction of scientific research for four decades—with rare exceptions.
CDC’s working case definition also held that any abnormal biological finding ruled out a diagnosis of ME. Architects of the CDC case definition displayed no signs of having undertaken even a cursory literature search in preparation for their influential document, which has been cited well over two-thousand times in other papers and became the most accessed paper in medicine the year of its publication. Reactivated herpes viruses, for instance, were by then a fairly uniform finding. In fact, people called ME “Epstein-Barr syndrome” in the 1980s. And while the same finding was fairly standard in AIDS and interpreted as immune damage, the government studiously ignored the finding in ME. Federal policy makers went on to bifurcate numerous signs and symptoms common to both AIDS and ME that way, citing AIDS signs as defining markers of the disease, while shoving identical data observed in ME into the trash as either incomprehensible or unimportant.
In 2025, CDC’s diagnostic guidelines continue to include subjective symptoms exclusively. The guidelines state unequivocally, “There is no specific test to diagnose ME/CFS,” and avoid proposing blood or imaging tests to help with the diagnosis.
What is peculiar about the government’s position is that it is common clinical practice to employ a combination of tests to achieve an accurate diagnoses in many if not most diseases—especially if the precise cause remains elusive. In making an MS diagnosis, for instance, doctors use a combination of clinical and neurological examinations and MRI brain scans to arrive at a diagnosis. A diagnosis of Myasthenia Gravis, too, requires a combination of tests.
Although ME now afflicts more than one in every one hundred Americans, a phenomenal prevalence rate, there has been no effort by federal agencies to identify a combination of blood assays, scans and clinical signs that would help inexperienced doctors identify ME. Excellent doctors over the last few decades have specialized in ME and learned to make a diagnosis using a combination of tests. The government might have convened these specialists at interludes and learned from them. Instead, in the world of ME, the U.S. government has chosen to issue heavy handed guidance while routinely shunning clinical expertise—with predictable results.
Apparently, lacking intervention, the government will hew to diagnostic nihilism indefinitely. In that light, it is almost comprehensible why medical schools do not bother to teach student doctors anything about ME—even that it exists.
Further reading on ME and low blood pressure:
Chronic fatigue syndrome: comments on deconditioning, blood volume and resulting cardiac function (2014)
Thank you for this article Hillary. It continues to anger me that it's been 40+ years and there's been no concrete support or major breakthroughs for this terrible disease. What a disgrace.
What a frustrating phenomenon Myalgic Encephalomyelitis and politics worldwide is! I fear this is the way humanity will die, stealthily through the back door whilst everyone's looking after no one 💔 😔