MEGALOBLASTIC ANEMIAS

Megaloblastic anemia Automated printout WebPath Photo

Hypersegmented poly Pernicious anemia KU Collection

Hypersegmented poly Megaloblastic anemia WebPath Photo

Megaloblastic anemia WebPath Photo

This is a broad term for all problems in which the normoblasts (and, often, the other cells in the body) cannot synthesize DNA fast enough to keep up with the growth of their cytoplasm. ("Nuclear-cytoplasmic asynchrony". This is easily the most plausible explanation; remember you also need B₁₂ to do methionine and methyl-malonic acid). Although patients will be anemic, the baby cells (-"blast") end up big ("megalo-"), and a good pathologist can immediately recognize a "megaloblastic marrow smear" by the big, blue cells with lots of cytoplasm and immature-looking nuclei. (Polys and their precursors are big, too. You'll see pictures; I won't ask you to make the distinction on an exam.)

Regardless of the cause, expect to see:

• anemia (and maybe neutropenia and maybe thrombocytopenia)
• increased mean corpuscular volume (why?) with normochromia and considerable anisocytosis (ask a pathologist to show you a "macro-ovalocyte")
• hyper-segmentation of the neutrophil and eosinophil nuclei (why?)
• shortened red cell survival time (often, much of the hemolysis takes place in the marrow; the marrow may appear hypercellular and serum LDH-1 levels, suggestive of hemolysis, can be extremely high)

Rule: Count one hundred neutrophils. Separate segments are defined to be masses separated by a thread composed entirely of heterochromatin. If you see one neutrophil with six segments, or five with five segments, you have established the diagnosis of megaloblastic anemia. I think a three-lobed eosinophil does it, too.



Pernicious anemia ("true pernicious anemia", "addisonian pernicious anemia", etc.)

This is extremely common, especially in older folks; one group argues that there must be 800,000 undiagnosed cases (Arch. Int. Med. 156: 1097, 1996). Once dreaded and very lethal ("pernicious"), the available of injectable B₁₂ (in the old days, a pound of raw liver per day by mouth, or liver injections) has now rendered this common problem almost innocuous.

The basic problems is chronic atrophic (usually autoimmune; most (>90%) of these patients have antibodies against the parietal cell canaliculi) gastritis with destruction of the parietal cells and failure of intrinsic factor production.

Often (maybe 40% of the time) there is some antibody that sticks to intrinsic factor as well, preventing its binding to B₁₂ ("blocking antibody", * type I's). There's also likely to be antibodies against receptors in the ileum where the complex must be absorbed ("binding antibody", * type II's). Assay J. Clin. Path. 46: 45, 1993 (* contrary to older sources, either can be present without the other).

* While we are ordering unnecessary lab tests, most of these patients have elevated serum gastrin levels, too (why?).

In addition to the problem making good blood cells, B₁₂ deficiency (from whatever cause) is noxious to the brain and cord, probably because of increased levels of methyl-malonic acid and propionic acid. Demyelinization of the posterior columns of the spinal cord happens early and causes loss of proprioception and some paresthesias, as in tabes dorsalis. Eventually, dementia occurs. These problems may precede the anemia (Postgrad. Med. 91: 231, 1992; Postgrad. Med. 88: 147, 1990).

In the 1980's, I had the rare privilege of autopsying a "virgin" pernicious anemia patient, a gentleman who was institutionalized for five years with "Alzheimer's disease". His physicians drew blood from time to time, but never noticed the anemia, the MCV of 140, or the hypersegmented neutrophils reported by the lab. Bad care. I noted each of the following "classic" changes:

• findings of anemia (pallor of all organs, big heart)
• slight icterus (why? ever hear of the "lemon yellow" pernicious anemia patient?)
• peripheral smear (from life) with macro-ovalocytes
• neutrophils on peripheral smear with 6-10 segments
• hypercellular, megaloblastic marrow;
• glossitis (can't replace those stratified squamous cells fast enough)
• autoimmune-style chronic gastritis ("fundic"; "type A"; achlorhydric) with some intestinal metaplasia
• immature, large nuclei in the remaining stomach epithelial cells
• loss of myelin in the posterior columns

NOTE: Often the lateral columns are affected, too, though less dramatically. This is called "subacute combined degeneration of the cord", typical of B₁₂ deficiency.

To make the diagnosis, physicians who practice good medicine perform the two-part Schilling test.

Give the patient an injection of normal B₁₂ first (why?)

Then administer radioactive B₁₂ by mouth. A healthy person will excrete the radioactivity in the urine. If your patient, for any reason, cannot absorb B₁₂ via the gut, the urine will not be radioactive.

If your patient cannot absorb B₁₂ via the gut, then give him or her a dose of radioactive B₁₂ with intrinsic factor. If this causes the radioactivity to appear in the urine, you know the patient lacks intrinsic factor. If the radioactivity still fails to appear, you know there's some problem with absorption (i.e., one of those antibodies and/or some disease of the gut).

It's common knowledge that patients with autoimmune gastritis, whether or not they have pernicious anemia, are at substantial risk for gastric cancer (carcinoma, carcinoid; see for example Cancer 71: 745, 1993 and Arch. Path. Lab. Med. 113: 399, 1989). It's ironic that, while the Japanese endoscope almost everybody (and often finding the highly-curable early gastric cancer lesions), we're just now getting used to the idea of endoscoping pernicious anemia patients regularly. For some better-late-than-never common-sense see Gut 34: 28, 1993; endoscopy every five years, more often if dysplasia is found, seems reasonable (Gut 31: 1105, 1990; Bill and Hillary take notice).

Classic "addisonian" pernicious anemia is primarily a disease of people of northern European ancestry, though any race can be affected. The sex ratio is about equal, which is unusual for an autoimmune disease.

"Juvenile pernicious anemia" mimics the adult disease in its hematologic and nervous system manifestations. These patients don't usually have autoimmunity, but instead are born without good intrinsic factor, or without receptors for the complex. Tip: Check the urine for methyl-malonic acid (why?)

Other causes of B₁₂ deficiency

"Inadequate diet" must be extreme. "Vegans", who will take no food of animal origin, get B₁₂ deficiency after a few five years unless they supplement. B₁₂ deficiency is common in today's "amateur" vegans, many of whom are teens (Am. J. Clin. Nutr. 76: 100, 2002).

If your whole stomach is gone after some big operation, you'll need B₁₂ supplementation, of course. But this isn't true pernicious anemia.

If you have malabsorption (sprue, Whipple's, lymphoma, scleroderma, others), or if you have the fish tapeworm on board, or if you have a blind loop (post-surgery, duodenal diverticula) full of bacteria, or if your ileum is messed up badly by Crohn's disease, you may need B₁₂.

* "Big Robbins" cites "increased need for B₁₂" in carcinomatosis, hyperthyroidism, and pregnancy. I've never seen this as a clinical problem, and because the vitamin is so available, I doubt its seriousness.

There's a good serum assay for B₁₂. It's expensive, but perhaps an occasional screen is worthwhile, more for the mental problems that the deficiency causes especially in the elderly. I'd prefer you start your anemia workup with a reticulocyte count first.

* Hey Doc! Want to keep your poorly-educated patients happy and coming back ($$)? Some physicians diagnose "pernicious anemia" wantonly, and prescribe monthly B₁₂ shots, which are red (ooh, pretty), painless, inexpensive, and harmless. Further, once you start doing this, it'll be hard to prove the patient didn't originally need the treatment and doesn't need to continue. However happy this common practice may make people, I have a ninth commandment problem with it. I hope YOU do, too.

Folic acid deficiency (ever know someone who called it "vitamin P"? "folic" means "from (green) leaves")

This is disturbingly common in the U.S., and not just in the alcoholics, oldsters, and babies cited in "Big Robbins". Contrary to your text, the deficiency need not be "gross". You need some vegetables in your diet every once in a while, and many Americans don't like them. (In the poor nations, many people can't afford them.) If you lack folic acid, you can't shuttle your one-carbon units (i.e., methyl and formyl groups) around.

In pregnancy, the fetus leeches out Mom's folic acid, which may already be in short supply. Likewise, in hemolytic disease and in carcinomatosis, folic acid supplies often drop, a "relative folic acid deficiency" is unmasked, and a superimposed megaloblastic state develops.

Phenytoin and the birth control pill are infamous for interfering with the absorption of folic acid. Of course, so can other malabsorption problems. Hemodialysis takes the vitamin out of the body, too.

A blood assays for folic acid is available. Again, it's expensive. I'd prefer you not order these for all your microcytic anemia patients at the onset of your workup. Tip: You can also detect folate deficiency by assaying the urine for formimino-glutamic acid (FIGlu), a breakdown product of histidine which requires folate for further processing.

BEWARE. Supplementing a patient with pernicious anemia with big doses of folic acid will improve the hematologic picture (nobody knows why) and exacerbate the brain disease (nobody knows why). This is the main reason that only small amounts of folic acid are put in over-the-counter not-for-pregnancy vitamins.

B₁₂ and folate-unresponsive megaloblastic anemia

Obviously, anti-DNA chemotherapy will produce megaloblastic changes.

* Anemias induced by chemotherapy tend to be undertreated, probably because they are difficult to treat. Perhaps the new, more-effective erythropoietin-like drug darbepoietin will prove helpful (Cancer 95: 613, 2002).

Occasional megaloblastic anemias respond well to vitamin B₁ (thiamine) or vitamin B₆ (pyridoxine). These are usually acquired, and probably reflect Nowell's law hits (i.e., there is an increased leukemia risk.)

Note: Heavy alcohol drinking, and sometimes liver disease (maybe) and hypothyroidism (maybe), will raise the MCV to maybe 110 fL. Nobody knows why.

IRON DEFICIENCY ANEMIAS

Pathology of Iron Metabolism WebPath Tutorial

Iron deficiency WebPath Photo

Iron deficiency WebPath Photo

Automated printout -- iron deficiency WebPath Photo

Iron deficiency anemia Peripheral smear KU Collection

You already know that iron is absorbed (in limited, regulated quantities) in the duodenum, shuttled around on transferrin, used in hemoglobin, myoglobin, and cytochromes, and the storage supply found to ferritin as the invisible short-term form ferritin and the copper-penny, Prussian-blue-stainable long-term form hemosiderin.

A person may become iron-deficient by:

• heavy menstrual loss (Shakespeare's Juliet had "green-sickness", iron deficiency signs attributed to being in love for the first time)
• abnormal blood loss (GI bleeding -- remember hookworm --, GU bleeding, uterine bleeding)
  Iron deficiency (mechanism still mysterious Am. J. Clin. Nutr. 72(S2): 549-S, 2000, may include GI and GU loss), hemolysis from pavement-pounding ("footstrike hemolysis"), and hemodilution by an expanded plasma volume (physiologic, to reduce whole blood viscosity for the best oxygen delivery) all contribute to "runner's anemia" (Ped. Clin. N.A. 49: 553, June 2002; JAMA case conference 286: 714, 2001).
• bad diet (there's not much iron in twinkies, fries, or diet pepsi; half of adults in the poor nations are iron deficient).
  Heme iron is much better absorbed than iron from beans. Especially, there is disappointingly little usable iron in spinach; what's there is oxalate-bound and unavailable

  Poor diet is seldom the sole cause in U.S. adults. However U.S. kids can and do become iron deficient, despite "Big Robbins"). There is very little iron in breast milk, and children do become deficiency as a result. No one knows the "best" amounts and timing for supplementation (Ped. Clin. N.A. 48: 401, 2001).

• malabsorption (sprue, those others)
• no HCl and/or no access of food to the duodenum (as after ulcer surgery)

Doc: If you find iron deficiency, you MUST find the cause. It is cancer of the GI or GU system until proven otherwise.

Around 10% each of toddlers, teenaged girls, and moms are iron deficient, and of these, around half are anemic (JAMA 277: 973, 1997). More numbers: Almost 20% of kids are iron-deficient, with 5% anemic (Clin. Ped. 44: 333, 2005); easy to diagnose, but these kids are still not beingfollowed up. Of course this is deplorable. An attempt by the English to alter the junk-food habits of their underclass through "education" was an expensive, complete failure (Arch. Dis. Child. 76: 144, 1997).

Regardless of the cause, the iron-deficient patient develops a hypochromic, microcytic (why?) anemia, which can be very severe.

You'll be impressed the first time you see tiny red cells with broad central pallor.

For some reason, elongated "pencil RBC's" are common in iron deficiency, and the platelet count tends to rise.



Textbooks describe a variety of additional physical findings that are supposed to be more or less specific for iron deficiency. This includes koilonychia (spoon-shaped nails), beefy glossitis, intestinal malabsorption, and upper esophageal webs ("Plummer-Vinson"; the link to iron deficiency is almost certainly a myth, and I have my doubts about the others, since they make no sense physiologically).

Plasma ferritin levels usually closely correlate with total body iron, provided that the liver isn't acutely damaged. More about iron testing when we cover lab testing.

* Tip: Allied health professionals often refer to both hemoglobin and hematocrit as "serum iron". I've given up trying to explain.

ANEMIA OF INFLAMMATION ("Anemia of Chronic Disease", Ped. Clin. N.A. 43: 623, 1997; Am. J. Med. Sci. 307: 353, 1994)

Here, there's plenty of iron in the body, but it isn't available to the normoblasts, but stays in the big fixed macrophage in the center of the erythroid island.

This unfortunate effect is mediated by increased body levels of interleukin 1 (* and probably other cytokines too), i.e., the macrophages are phagocytosing somewhere in the body, and the "acute phase reaction" has been going on long enough to cause lowering of the hematocrit.

* The primacy of the iron problem is confirmed by the use of zinc protoporphyrin (i.e., free porphyrin) levels as marker for anemia of chronic disease: Blood 81: 1200, 1993.

* There may also be a component of hemolysis (by those hungry macrophages) though I haven't seen increased reticulocyte counts in these folks. Or the kidney may not be making enough erythropoietin.

This is a common, often-overlooked / undertreated problem in AIDS (J. Inf. Dis. 185(S2): S-105 & S-110, 2002); perhaps the availability of newer erythropoietin-like medications will result in this being treated more effectively.

Patients have a hypochromic-microcytic (why?) anemia with a hemoglobin of around 8-10 gm/dL. Bone marrow iron stores are increased.

In the U.S., the usual causes are rheumatoid arthritis, osteomyelitis, TB, and huge bedsores. (Remember these also cause amyloidosis A; same underlying problem.) Treat the underlying cause, Doc.

* If you want to diagnose and monitor the disease, try serial zinc protoporphyrins (Blood 81: 1200, 1993; why does it work?)

* For tough cases, you can try erythropoietin.

SIDEROBLASTIC ANEMIA

Once again, there's plenty of iron in the body, and this time, it's even in the normoblasts. But in this relatively uncommon problem, patients have difficulty placing the iron into their heme rings. Instead, it remains in the mitochondria, which light up as Prussian-blue positive chunks in their ordinary position around the normoblast nucleus (hence the cute term "ringed sideroblasts").

Commonly, only some of the red cell precursors are affected (i.e., Nowell's law has been operating; these patients are probably at increased risk for leukemia.) Alcoholism and isoniazid therapy also get cited.



* In the X-linked hereditary sideroblastic anemia, the problem is with δ-amino levulinic acid synthetase (NEJM 330 675, 1994; Blood 90: 872, 1997; Blood 93: 1757, 1999). Some cases respond to big doses of pyridoxine, and in these cases, the pyridoxine binding site on the protein is what was hit by the mutation (of course). More on this: Blood 93: 1757, 1999.

PURE RED CELL APLASIA

In babies, congenital difficulty with erythropoiesis is the Blackfan-Diamond syndrome and variants.

The problem in common Blackfan-Diamond that the normoblasts undergo apoptosis unless they are awash with erythropoietin (Blood 83: 645, 1994; Blood 87: 2568, 1996; further complexities Blood 105: 838 & 4620, 2005).
* The gene is ribosomal protein S19: Nat. Genet. 21: 169, 1999.

* Another variant (autosomal dominant dyskeratosis congenita) lacks the ability to restore telomeres to the endlessly-dividing marrow stem cells (Lancet 359: 2168, 2002; Blood 102: 916, 2003).

In the Fanconi C variant, the red cells are oversensitive to signals from γ-interferon (and surely other stuff) to undergo apoptosis (Blood 90: 974 & 1047, 1997; Blood 88: 2298, 1996), etc., etc. There are at least 8 Fanconi anemia (red cell underproduction, fragile chromosomes) loci, all autosomal recessive (Am. J. Hum. Genet. 61: 940, 1997. * Hypoplastic anemia and an extra joint in the thumb: Aase syndrome!

In the chronic hemolytic disorders (notoriously sickle-cell disease, less often spherocytosis or hemoglobin C disease), the production of normoblasts can simply shut down, even when there's enough folic acid around. Parvovirus 19 is now known to be the usual cause. This is called aplastic crisis.

Future pathologists wishing to spot "parvo": You will see no normoblasts beyond the basophilic stage, and the basophilic normoblasts have the nuclear chromatin pushed to the edge by the viral inclusion.

Patients with thymoma / thymic hyperplasia often develop a red-cell aplasia, probably because T-cells attack the normoblasts in the bone marrow. Removing the thymoma often solves the problem (Am. J. Clin. Path. 103: 346, 1995).

Patients who take chloramphenicol can all expect some temporary suppression of erythropoiesis, and in 1 case in about 25,000 this is severe and permanent.

In kidney disease, there's often a lack of erythropoietin, and patients receive injections of the stuff, which helps.

* Some kidney patients treated with recombinant erythropoietin develop anti-erythropoietin antibodies and a severe aplastic anemia: NEJM 346: 469, 2002; responds to treatment Lancet 363: 1768, 2004.

Normal marrow Section WebPath Photo

Normal marrow Higher power, section WebPath Photo

Normal marrow Smear WebPath Photo

Normal marrow WebPath Photo

Normal marrow WebPath Photo

Rouleaux formation WebPath Photo

FINISHING UP: Thankfully, hemoglobins with excessively high oxygen affinity ("Chesapeake" and many others) are uncommon. As you'd expect, these render the patient polycythemic.

* Red-cell substitutes have been a disappointment. A bovine hemoglobin preparation delivers the goods but only lasts for a day in the bloodstream; it is now in use in some nations. The older perfluorocarbon emulsions ("Fluosol", others) required patients to breathe 100% oxygen which was deadly to the lungs. Review Am. J. Clin. Path. 118 S: S-71, 2002.

We'll do polycythemia vera, other secondary polycythemias, acquired aplastic anemia, and the myelodysplastic syndrome under "White Cells". Enjoy these pictures:

{13856} red cell, normal blood. (If platelets stick to polys, it's EDTA anticoagulant effect ("satellitism"). Some folks have a gene to make this happen.)

JEHOVAH'S WITNESSES AND BLOOD TRANSFUSION

Sooner or later, you will run into the issue of blood for Jehovah's Witnesses. The group is authoritarian, tightly-controlled, and forbids blood transfusions for its members.

Ask a spokesperson for the details. "Many Jehovah's Witnesses feel that accepting a blood transfusion will lead them to eternal damnation" (Ob. Gyn. 102: 173, 2003). Here are some references which will help you in your thinking.

On the one hand...

• It is hard not to admire people who give up their lives for moral principles -- even if the rest of us think they are misguided (even deceived). This is very clear in the case of a Jehovah's Witness freely refusing blood and dying as a result. US law is unequivocal in supporting the rights of adults to do this. Likewise, Jehovah's Witnesses around the world go to prison rather than serve in the armed forces. As a beginning Christian, I belonged to a pacifist denomination, and although I decided this position was wrong (at least for me), I retain a special admiration for anybody who takes the hard road because something else is of ultimate importance.
• For some reason that nobody has explained in the refereed medical literature, Jehovah's Witnesses are free to accept fractions made from red cells, from white cells, from platelets, or from plasma. However, they may not take any of the fractions themselves, or whole blood. They appear quite willing to accept stem cells from other people (Bone Marrow Transplantation 32: 437, 2003).
• Members believe that if a child is transfused, he/she can be "cut off" from the possibility of obtaining eternal life (J. Emerg. Med. 14: 251, 1996). In the 1980's, one spokesman told me that the child would be stigmatized, regarded as satanic, and that this was something to take into account before transfusing a child against the parents' wishes. More recently I have been reassured that this will not happen.
• There is a saying among blood bankers that we are the only business people in the community who work hard to reduce demand for our product. I never saw the point to most "routine" transfusions. So I was not at all surprised when a Portland bloodless surgery group found that Jehovah's Witnesses who had total abdominal hysterectomies without blood transfusions did as well as or better than controls who had transfusions (Am. J. Ob. Gyn. 180: 1491, 1999; plus, remember these folks don't smoke or drink). Obviously it would be stupid (at best) to generalize this to more serious surgery, or to hematologic disease.
• Very extensive surgeries can be performed without blood, especially when erythropoietin, hemodilution, and special coagulators are used (J. Ped. Surg. 32: 1759, 1997; Ann. Thoracic Surg. 69: 935, 2000). These also cost third-party payers lots of money (Br. Med. J. 318: 873, 1999). (Smokers and reckless skydivers also cost society extra.)
• Several sensitive articles have appeared which physicians may find helpful in understanding those whose values differ (a good one: Am. J. Psych. 156: 304, 1999).
• Be sure you do not confuse the JW position against blood transfusion with the beliefs of other sects against all medical interventions.
• Despite the fact that members insist they are "neutral" and have no loyalty to any secular government, they do point out that their legal battles have enlarged the freedoms of their neighbors (i.e., the government can't make your kids say the pledge of allegiance, and you can keep your kids out of the usual extracurricular activities even if they want to participate.)
• Unlike other militants (the anti-biotechnology people, the anti-animal-research people, the anti-stem-cell people), the Jehovah's Witnesses are not trying to force ideology and disinformation campagin everybody else, or interfere with medical progress. For this reason alone, I urge you to respect them.

On the other hand...

• No reasonable person questions that blood transfusions save lives, and sometimes are necessary to save lives. Members do die because they refuse transfusions, and not because of lack of surgical skill. I cannot address the spiritual issues. But literature which I've seen from the Jehovah's Witnesses on the risk-benefit ratio for transfusions in very-sick people seem to me to be one-sided at best.
• A Jehovah's Witness woman is 44x more likely to die in childbirth than a woman who will accept a blood transfusion (Am. J. Ob. Gyn. 185: 893, 2001 -- as you'd expect, a plan to "optimize hemoglobin using erythropoietin prior to delivery" in these women was a dismal and expensive failure)
• In Italy (and probably elsewhere in Europe), most physicians will not even undertake the workup of an adult JW with likely leukemia, because of all the problems that blood refusal will create. (In the US, this probably shocks us, but think about it. Problems range from additional public expense to increased likelihood of a bad outcome to dealing with militants and snoops to watching somebody actually die of anemia or thrombocytopenia as a result of your chemotherapy and being forbidden to save them.) A team in Milan has actually developed a protocol for JW's with adult leukemia: Eur. J. Haem. 72: 264, 2004, and has gotten some complete remissions; they argue that hematologists should reconsider the boycott and I'm inclined to agree.
• In Bulgaria, the Jehovah's Witnesses accepted a government condition, allowing them to collect money and proselytize only if they promised not to punish members who received blood transfusions. This may now be official policy worldwide (Lancet 356: 1114, 2000). The denomination used to forbid immunizations and organ transplantations, but has reversed itself. In the 1930's, the denomination conducted an inflammatory disinformation campaign against aluminum cookware. With no basis in fact, the JW's smeared the medical profession as evil conspirators against the health of the public. This is now history. Perhaps the position on transfusion will change too. So far as I know, all sects have made ghastly mistakes at one time or another. Some acknowledge their past errors. Others don't.
• Since 1961, any adult member who accepts a blood transfusion knows he or she will be disfellowshipped and shunned. For example, the member will not get to go to his/her children's weddings or his/her parents' funerals. The marriage will probably break up, the rest of the family will try to keep the children away from the disfellowshipped parent, and friendships will end. When a Jehovah's Witness is in the hospital, the "visitation committee" comes around to remind doctors not to transfuse their fellow-believer, and of course to snoop and be sure there's no transfusion. With pressures like this, I think reasonable people can ask whether refusing a needed transfusion is really a free choice.
• A group within the Jehovah's Witnesses sect which accepts blood transfusions remains entirely anonymous -- if any member of this group were to use his/her name in public, he/she would be disfellowshipped and lose his/her family as a punishment (J. Med. Ethics 26: 375, 2000). One member was disfellowshipped simply for writing a supportive e-mail to the group -- his wife turned him in. One ethicist suggests that physicians need to tell Jehovah's Witnesses that the group exists (J. Med. Ethics 26: 299, 2000) -- I agree but doubt this would have any effect.
• Please remember that for any denomination, the leadership is not the members. Where dissent is not tolerated, you cannot know the hearts of the faithful. I have found individual members to be motivated by an uncommon concern for my own spiritual well-being, which I appreciate despite my disagreements. However... the denominational leadership often finds itself under sharp public criticism. In 1987, it expressly instructed members who work in the health-care setting to breach medical confidentiality. In the cited example, a member who learned that another member had an abortion was expected to announce this to the congregation. Of course this is a crime in many jurisdictions (J. Med. Ethics 26: 381, 2000), and as a physician, simply having people like this around me makes me extremely uncomfortable. When one ethicist suggested a don't ask, don't tell approach for Jehovah's Witnesses needing blood (J. Med. Ethics 25: 469, 1999), the denomination's lawyers responded with a piece (J. Med. Ethics 25: 463, 1999) full of more venom and obvious distortion than I had ever seen in a journal article. Letting children know that they are set apart from an evil world includes requiring them to leave the classroom during other children's birthday parties. Most are not allowed to participate in sports or extracurricular activities, i.e., the situations in which they would probably develop friendships with non-JW's. There are over 1000 divorce actions in the US each year because one partner embraces the sect and the other does not, and these tend to be extremely bitter. Beginning in 2001, the media gave a lot of attention to the supposed massive protection of pedophiles and punishments meted out to the children who bring accusations even if they're probably true. As we've seen before, this is a politicized subject where it's often hard to get at the truth. But as of April 2002, despite the resignation of church leader William H. Bowen over the issue, the main JW internet site continues silent. And right or wrong, people seem to judge the denomination by its focus on direct put-you-on-the-spot, proselytization and staying uninvolved with our tolerant, pluralistic mainstream society rather than community service and philanthropy. The notions of altruism, kindness to strangers, and universal love -- which are absolutely central to all the major world-faiths -- are conspicuously absent from what I've read of their literature. However, I have known several individual members who have been among the nicest people I've known, and during the years when I considered a pacifist commitment, I came to admire them very much. The denomination also teaches that family members who accept transfusion or drop membership should be killed by stoning, and the fact that they do not do so is merely because national law forbids it. In France and Italy, most physicians simply transfuse Jehovah's witnesses while they're asleep in surgery, without telling them or simply lying (Eur. J. Anaesth. 8: 297, 1991; Med. Educ. 36: 479, 2002). I find this unacceptable; others may disagree, feeling that these people's choice -- in contrast to the choices your physician must offer you -- is neither honestly-informed nor free.
• The most helpful article I've found is J. Med. Eth. 24: 295, 1998. The author urges physicians to help patients make a genuinely free, informed decision by conferencing with them, giving accurate information, and asking them why they believe as they do and what pressures are on them. Whatever decision the adult patient reaches must be honored.

{13858} red cell, normal marrow, unusual stain
{13976} red cell, normal blood (two orthochromatic normoblasts)
{20780} red cell, normal blood
{46538} red cell, normal blood
{26161} basophilic normoblast (prorubricyte)
{26162} basophilic normoblast (prorubricyte)
{26197} basophilic normoblast (prorubricyte)
{26198} basophilic normoblast (prorubricyte)
{26223} polychromatophilic normoblast (rubricyte)
{26224} polychromatophilic normoblast (rubricyte)
{18690} orthochromatophilic normoblast (metarubricyte)
{10127}red cell, even staining for hemoglobin

{10130} Heinz bodies
{10418} nucleated red cells in hemolytic disease of the newborn
{21113} hemolytic disease of the newborn
{13898} polychromasia (the purple, large red cells are "reticulocytes")
{14722} reticulocytes, normal
{14723} reticulocytes, too many
{39616} erythroid hyperplasia
{39617} erythroid hyperplasia

{27434} plasmodium vivax
{13880} cold agglutinins in the blood
{12299} hereditary spherocytosis
{16172} spherocytes
{11547} hereditary elliptocytosis (spherocytosis variant)
{13892} hereditary elliptocytosis (spherocytosis variant)
{12305} spur cells ("acanthocytes"' E.T.-finger cells); abetalipoproteinemia case
{13871} abetalipoproteinemia smear (lymphocyte in upper right)
{20128} abetalipoproteinemia smear

{17419} sickle cell disease
{13907} target cells
{16167} target cells
{16177} target cells
{16169} stomatocytes (flattened uniconcave RBC's typical of acute drunkenness, liver disease and various rarities, everyone's allowed a few)
{12308} schistocytes
{13895} schistocyte
{16178} schistocytes
{17137} DIC
{20149} thalassemia
{13877} basophilic stippling
{10430} "megaloblasts" (i.e., the red cell precursors in pernicious anemia)

{13751} megaloblastic blood smear
{13754} megaloblastic marrow
{13757} megaloblastic marrow
{13889} macro-ovalocytes (i.e., megaloblastic anemia)
{12302} teardrops

{14013} sideroblastic blood (dimorphic RBC population)
{27342} ringed sideroblasts, iron stain (not the greatest photo)
{09054} iron in mitochondria
{14025} Pappenheimer body (retained iron-loaded mitochondrion, i.e., you have sideroblastic anemia and/or have had a splenectomy; you need a Prussian blue stain to see them well)
{16168} Pappenheimer bodies
{13854} polycythemia vera blood
{13976} rouleaux
{14028} multinucleated red cell (DiGuglielmo's?)
{23920} myelodysplastic syndrome
{13883} Howell-Jolly bodies (stray chromosomes not extruded; usually mean the patient has had a splenectomy and they were not removed)

{16170} Howell-Jolly bodies
{13904} post-splenectomy
{29011} blood bank

Howell-Jolly bodies and nucleated red

WebPath Photo

Let the young sing songs of death. They are stupid. The finest thing under the sun and the moon is the human soul. I marvel at the small miracles of kindness that pass between humans. I marvel at the growth of conscience, at the persistence of reason in the face of all superstition and despair. I marvel at human endurance.

-- Anne Rice, Pandora ("The Vampire Chronicles")