Deciphering polycythemia.

Most causes of an elevated hematocrit can be determined with a simple workup that includes a complete blood count and chest x-ray. However, measurement of red blood cell mass and plasma volume is required to differentiate primary, secondary, and combined polycythemia. Phlebotomy is customary for primary disease and some secondary cases in which the underlying cause cannot be removed.

Recent-onset myelodysplastic syndrome mimicking acute leukemia during infection.

A previously healthy 74-year-old patient without a prior history of hematological disease presented with an acute respiratory infection. Peripheral pancytopenia led us to perform a bone marrow biopsy, and the diagnosis of undifferentiated acute myelogenous leukemia (AML, 61% blasts) was made. Following antibiotic treatment and resolution of the infection, the blast count in the bone marrow fell to 2%, leaving a clinicopathologic picture consistent with myelodysplastic syndrome (MDS, French-American-British type refractory anemia), and the patient survived for a total of 16.5 months following the initial presentation with cytokine support. A preterminal blast proliferation occurred during a bacterial ear infection and rapidly responded to a withdrawal of cytokine support, antibiotic therapy, and hydroxyurea. The patient succumbed ultimately to an apparent myocardial infarct. Clinicians should consider transient acceleration of MDS in their differential diagnosis when confronted with apparent AML and acute infection.

Efficacy of alpha interferon and hydroxyurea in late phase refractory myeloproliferative disease.

Three patients are described with late-stage myeloproliferative diseases, two with accelerated phase chronic myelogenous leukemia (CML) and one with refractory polycythemia vera (P vera), who achieved hematologic control after the addition of interferon (IFN) to hydroxyurea therapy. Both the CML patients continue to have a sustained clinical remission at 12 and 38 months. The patient with P vera had failed several previous treatments including busulfan, P32, hydroxyurea, and anagrelide, but became responsive after interferon use followed by reintroduction of hydroxyurea. Our observations support the efficacy of IFN alpha and hydroxyurea combination in late-phase myeloproliferative disease and warrants further clinical investigation.

Investigations on the role of hemopexin and albumin in plasma clearance and tissue distribution of Sn-protoporphyrin.

The mechanism of the clearance of circulating tin-protoporphyrin (Sn-PP), a competitive inhibitor of heme oxygenase in the degradation of heme to bilirubin, is unknown. Two serum proteins, albumin and hemopexin, which are instrumental in the delivery of iron-protoporphyrin (heme) to the liver, also bind metalloporphyrins with high affinity and may aid in targeting their tissue distribution. After intravenous injection of 1 mumol Sn-PP/kg, the serum concentration of hemopexin decreased in human subjects, rats, and rabbits within 24 hours to a similar extent (30% to 50%). This finding suggested that hemopexin may have a role in the tissue distribution of Sn-PP. However, when rats were injected with Sn-PP in saline solution or complexed with albumin, more Sn-PP was taken up by the liver and testes than when Sn-PP was complexed with hemopexin. These results indicate that hemopexin does not preferentially target Sn-PP to the liver and may not be the preferred vehicle for clearance of circulating Sn-PP.

Polycythemia vera and other polycythemic states.

The diagnosis of polycythemia requires an accurate and independent assessment of both plasma volume and red blood cell mass. Patients with an increased red cell mass (absolute polycythemia) may be hypoxic or have an erythropoietin-secreting tumor or space-occupying lesion compressing the kidney. Those with a reduced plasma volume (relative polycythemia) most often are tobacco smokers, are taking diuretic or cardiac medications, or ingest increased quantities of caffeine-containing beverages. On the other hand, polycythemia vera is a systemic disease with multiple complications, which is best diagnosed through a complex of findings as outlined by the Polycythemia Vera Study Group.

Targeting of heme oxygenase inhibitors to the spleen markedly increases their ability to diminish bilirubin production.

Incorporation of heme oxygenase inhibitors into phosphatidyl choline liposomes markedly enhanced localization of these agents within the spleen as compared with the localization observed following their administration in aqueous vehicle. The increased concentration of inhibitor within splenic microsomes led to a near complete and sustained blockade of heme oxygenase activity and thus to a marked diminution in biliary bilirubin output. These studies suggest that heme oxygenase inhibitors administered within liposomes may so effectively block bilirubin production in the human newborn that ancillary methods for treating this important clinical problem may be reduced to a minimum.

Factors that accelerate or retard red blood cell senescence.

This article explores information concerning alterations in the time of age-related red blood cell (rbc) death (rbc senescence) in experimental animals and humans. Those factors that accelerate or retard the mean time for senescent death [the mean potential rbc life-span, (T)] are discussed; specifically excluded are conditions in which rbc survival is shortened due to an increase in the rate of age-independent [random hemolysis, (k)]rbc death. The factors prolonging senescence are reduction in metabolic rate through hibernation, reduced environmental temperature, hypophysectomy and thyroidectomy, and splenectomy. In general, these processes prolong rbc senescence by about 10%-15% in the models studied to date. The failure of splenectomy to prolong rbc senescence to any physiologically meaningful extent casts serious doubt on the concept that splenic processes are a major factor in the senescence process. Rbcs made under conditions of increased erythropoiesis and/or increased metabolic rate show acceleration of senescence. Thus, rbcs of animals treated with thyroxine show a 15% acceleration of senescence. "Stress reticulocytes" and normal full-term human newborn rbc may show up to 25% reduction in (T). The maximum acceleration seen to date is 50%-90%, as seen in the rbcs of the fetal and newborn rat. rbc senescence is not accelerated in rats with splenomegaly and increased rates of random hemolysis, again casting strong doubts on the spleen's ability to alter rbc senescence by progressively modifying the rbc during successive passages through that organ. It is postulated that rbc senescence is mainly a function of the red cell's initial endowment, particularly in the dynamic ability of that cell (and its membrane) to adapt to cumulative stresses that exist during its circulation through the body.

Proof that Sn-protoporphyrin inhibits the enzymatic catabolism of heme in vivo. Suppression of 14CO generation from radiolabeled endogenous and exogenous heme sources.

Sn-protoporphyrin (SnPP) suppresses generation of 14CO from hepatic heme labeled with delta-aminolevulinic acid (5-[14C]ALA) or from infused [14C]hemin in rats. SnPP administered 1 h before administration of 5-[14C]ALA virtually abolished the peak output of 14CO occurring 2-3 h after injection of this heme precursor, and during the succeeding 12 h reduced 14CO excretion by approximately 61% compared with controls. When [14C]hemin was infused, SnPP diminished 14CO excretion by approximately 50%. These findings, derived from experiments using radiolabeled endogenous and exogenous heme sources, establish conclusively that the synthetic metalloporphyrin SnPP inhibits the oxidative degradation of heme in the intact animal.

Thrombotic thrombocytopenic purpura: treatment with plasmapheresis.

Twenty-one episodes of thrombotic thrombocytopenic purpura (TTP) were treated with plasmapheresis. Adjunctive agents included corticosteroids, aspirin, dipyridamole, and vincristine. There were 17 patients; 12 were female. The median age was 41 years. Most patients presented with neurologic symptoms. Thrombocytopenia was profound with a mean initial platelet count of 14,900/mm3. The mean hematocrit on presentation was 26.7% and the mean LDH 1300 IU/L. Eighteen episodes responded completely following plasmapheresis/plasma exchange (86%). Response was prompt, the initial rise in platelet count occurred after a mean of four exchanges, and complete response (a platelet count over 150,000/mm3) was obtained after a mean of nine exchanges. Four of the episodes treated were relapses that occurred in three patients. All responders are alive with a median duration of follow-up of 20 months. The three patients who failed to respond have died. This report extends recent observations that the addition of plasmapheresis/plasma exchange to the therapy of TTP has significantly improved the outlook for patients with this disorder.

Analysis of publication output of internal medicine faculty members.

The number of publications per year produced by a department of internal medicine faculty is analyzed. The output of the younger faculty members (40 years or less) averaged 1.4 publications a year, and the annual output of the older faculty (over 40 years) averaged 2.3 publications (p less than 0.05). The site of their primary clinical responsibilities did not significantly affect their publication productivity. In all subspecialty sections, the output of older faculty members correlated well with that of younger faculty members (p less than 0.005). The productivity of section chiefs correlated well with the productivity of younger faculty members in their respective sections (p less than 0.001). Younger faculty members who later entered private practice had a lower (p less than 0.02) publication output than those who left for another academic position. The output of faculty members is related to the age of the faculty members, overall sectional productivity, and productivity of the section chief.

Bupivacaine alters red blood cell properties: a possible explanation for neonatal jaundice associated with maternal anesthesia.

Cord blood was incubated with lidocaine, mepivacaine, bupivacaine, or buffer and red blood cell filterability was determined. Only bupivacaine at either 1 or 2 micrograms/ml prolonged filterability by an average of 58 to 65% over red cells treated with buffer alone. Tritiated bupivacaine was bound to a greater extent to red cell ghosts from cord blood (24.6 +/- 5.8%) than to adult red cell ghosts (14.6 +/- 2.6%). Finally, we determined red cell survival in 13-day-old rats injected with bupivacaine or buffer. At 2 h after injection, buffer-treated animals had a red cell survival of 96.9 +/- 3.3%, whereas 2-h survival was reduced to 82.6 +/- 8.7% for the animals injected with bupivacaine. Our results suggest that the neonatal jaundice associated with maternal anesthesia, especially bupivacaine, may be related to the observations that these agents cross the placenta, bind to the red cell membrane and reduce its filterability, resulting in shortened red cell survival.

Increased Heinz body formation and impaired erythrocyte pentose phosphate shunt function during pregnancy.

The erythrocytes of 90 pregnant women were evaluated for the presence of in vivo or in vitro oxidant damage. The reduced glutathione (P less than 0.005) and the membrane reduced sulfhydryl (P less than 0.001) concentrations were decreased in fresh erythrocytes. Following incubation with acetylphenylhydrazine, Heinz body formation was significantly increased (P less than 0.001). Both the increase in Heinz body formation and the reduction in membrane reduced sulfhydryl content correlated strongly with duration of pregnancy. Glucose consumption was significantly decreased before, but not after, new methylene blue stimulation. Pentose phosphate shunt activity was impaired both before (P less than 0.05) and after (P less than 0.001) stimulation. No changes were observed in pentose phosphate recycling. The only alteration observed in the activity of the enzymes of the pentose shunt was an elevation of 6-phosphogluconate dehydrogenase activity. Although the clinical significance of these findings remains to be determined, medications with an oxidant potential should be used judiciously during gestation.

Effect of acetaminophen toxicity on erythrocyte osmotic fragility in the Fisher rat.

The protective effect of propylthiouracil (PTU) pretreatment against acetaminophen-induced erythrocyte osmotic fragility was determined in the male Fisher rat. Hepatotoxicity was assessed for comparative purposes. PTU (0.15%) was fed in chow for a period of 12 days. Acetaminophen (1 g/kg body wt) was then administered orally by a stomach tube after an overnight fast. The rats were killed either 4 or 24 hr later. Erythrocyte osmotic fragility was determined by the extent of hemolysis in various concentrations of NaCl solutions. Hepatotoxicity was assessed by a rise in serum transaminases and by histological examination of hepatic tissue. PTU treatment when compared with control not only protected rats against acetaminophen-induced hepatotoxicity as reported before, but also protected against erythrocyte osmotic fragility. The time course of acetaminophen toxicity seems to be similar for liver and erythrocyte since both showed damage after 24 hr but not after 4 hr of acetaminophen administration. The data show that PTU pretreatment affords protection against acetaminophen-induced increased erythrocyte osmotic fragility even when their glutathione concentrations were not significantly different, suggesting that PTU per se has a protective effect.

Neurologic manifestations of essential thrombocythemia.

Essential thrombocythemia is a clonal myeloproliferative disorder, characterized predominantly by a markedly elevated platelet count without known cause. We report a case that was recognized during investigation of a transient ischemic attack, and review the neurologic findings in 33 patients with unequivocal essential thrombocythemia under prospective study by the Polycythemia Vera Study Group. Twenty-one patients had neurologic manifestations at some point during their course, including headache (13 patients), paresthesiae (10), posterior cerebral circulatory ischemia (9), anterior cerebral circulatory ischemia (6), visual disturbances (6) and epileptic seizures (2). All patients with neurologic symptoms responded satisfactorily to treatment, although continuous or repeated treatment was often required. Therapeutic recommendations include plateletpheresis for major thrombo-hemorrhagic phenomena, or megakaryocyte suppression with radioactive phosphorus, alkylating agents (such as melphalan), or hydroxyurea; minor symptoms may respond to platelet antiaggregating agents.

Relative anemia and iron deficiency in cystic fibrosis.

Significant alterations in hemotologic function in cystic fibrosis are suggested by the observation that polycythemia is uncommon, even among cyanotic patients. To elucidate those factors that influence hematologic equilibrium, 39 stable patients with cystic fibrosis were evaluated with regard to hemoglobin, hematocrit, RBC indices, reticulocyte count, serum iron and total iron binding capacity, serum ferritin, vitamin E, and carboxyhemoglobin levels. Hemoglobin concentrations were below the 50th percentile for age in 90% of the patients, including the 23% who were cyanotic. Serum ferritin levels were below the mean for age in 85% and below 12 ng/mL in 33% of patients. Vitamin E levels were less than 5 micrograms/dL in 33%, indicating deficiency. Carboxyhemoglobin values were elevated in 64% of the patients. These data indicate that relative anemia is common in cystic fibrosis and suggest that iron and vitamin E deficiency may contribute to that anemia. Twenty-two patients with cystic fibrosis were then given 2 weeks of oral iron therapy followed by two to three additional weeks of iron and vitamin E. This therapeutic trial resulted in an increase in mean hemoglobin concentration from 13.87 to 14.50 g/dL (P less than 0.01) associated with a significant increase in levels of serum ferritin (P less than 0.001). The increase in hemoglobin occurred primarily during the second 2 weeks when patients were receiving both iron and vitamin E. However, we were unable to document evidence of increased hemolysis when patients were receiving iron therapy alone. This response to oral iron therapy is confirmation that iron deficiency contributes to the failure of some patients with cystic fibrosis to compensate hemotologically for hypoxia.