Predicting therapeutic efficacy for sickle cell anemia.
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Anemia, Sickle Cell↗
Biomedical subjects
G P Rodgers
Publications and source records attributed to G P Rodgers.
Intracellular polymerization of sickle hemoglobin: disease severity and therapeutic goals.
We have demonstrated that the extent of intracellular polymerization of deoxyhemoglobin S can be predicted from knowledge of intracellular hemoglobin concentration, composition and oxygen saturation. Furthermore, we have demonstrated that polymer, which appears to be the main determinant of abnormal red cell rheology, can be detected in sickle erythrocytes at high oxygen saturation values and is not significantly affected by membrane and other cellular constituents. Some of the factors which modify the pathophysiology of sickle cell anemia can be classified as genetic or cellular. To analyze in more detail the genetic factors, we examined 12 sickle syndromes. When the effects of these genotype differences are analyzed for their changes in hemoglobin composition and concentration, we found that polymer formation can account for 80% of the variation in hemolytic and clinical severity. Cell heterogeneity can also modify polymer formation. The premature increases in erythrocyte density (intracellular hemoglobin concentration) in sickle cell anemia increases polymerization tendency. Homozygous alpha-thalassemia in sickle cell patients reduces this increase in cell heterogeneity and improves the hemolytic aspect of the sickle cell disease. For homozygous sickle cell patients we find that the broader density distributions (higher degree of cell heterogeneity) are associated with those cell populations with greater tendency of polymer formation. However, the major utility of our knowledge of intracellular polymerization appears to be its value in defining quantitatively the goals of the major therapeutic approaches with respect to how much inhibition of polymerization would be necessary to achieve various levels of amelioration of disease processes. The primary determinant of the amount of polymer formation within the SS erythrocyte is the extent of oxygen saturation. We measured intracellular polymer formation in SS erythrocytes using carbon-13/proton double nuclear magnetic resonance. As the oxygen saturation is decreased below about 90% oxygen saturation, we begin to see the appearance of polymer which steadily increases with decreasing oxygen saturation. The total intracellular hemoglobin concentration also affects the amount of polymer formed. By examining polymer formation in fractionated subpopulations of SS erythrocytes at various density values (or intracellular hemoglobin concentrations) we demonstrated that the polymer fraction increased with increasing intracellular hemoglobin concentration for any given oxygen saturation.(ABSTRACT TRUNCATED AT 400 WORDS)
Anemia, Sickle Cell↗
Amniotic fluid embolism.
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Embolism, Amniotic Fluid↗
Hemoglobin SC disease and alpha-thalassemia. Prolonged survival and mild clinical course.
An 86-year-old black woman admitted for an elective cataract extraction was found to have moderate hypochromic microcytic anemia. Hematologic evaluation disclosed the presence of hemoglobin SC disease and heterozygous alpha-thalassemia-2 (alpha alpha/alpha-). A red cell density profile of the patient's peripheral blood revealed an absence of the typical uniform shift toward higher-density values seen in hemoglobin SC disease, indicating a "normalization" in the distribution of intracellular hemoglobin types. It is suggested that the co-inheritance of hemoglobin SC disease and heterozygous alpha-thalassemia-2, probably by decreasing the tendency toward intracellular hemoglobin S polymerization, contributed to her prolonged survival and relatively mild clinical course.
Aged↗
Accumulation of nifedipine after multiple doses.
The single and multiple dose pharmacokinetics of oral nifedipine capsules, 10 mg, have been examined in five patients with peripheral vasospasm. After a single dose, nifedipine was rapidly absorbed in three and slowly absorbed in two patients. Mean bioavailability parameters included a tmax of 2.9 h, a Cmax of 33.3 ng ml-1 and a AUC0-8 h of 113.3 ng h ml-1. After multiple dosing with either 10 or 20 mg every 8 h for 10 days the mean tmax at steady state was 2.1 h while the mean dose-corrected (to 10 mg) Cmax and AUC0-8 h were 51.9 ng ml-1 and 146.9 ng h ml-1, respectively. The mean elimination rate constant was 0.173 h-1 after both single and multiple doses. The mean extent of accumulation of nifedipine, defined as the ratio of AUC0-8 h (steady state)/AUC0-8 h (single dose), was 1.3; we concluded that nifedipine accumulates in the body when it is administered every 8 h. This should be taken into account when predicting steady state serum concentrations and haemodynamic effects of nifedipine from single dose kinetic data.
Adult↗
Deoxyhemoglobin S polymer formation in sickle cells.
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Anemia, Sickle Cell↗
Irreversibly sickled erythrocytes in sickle cell anemia: a quantitative reappraisal.
Irreversibly sickled cells (ISCs), considered by some to be of major pathophysiologic significance, have been reported to comprise between 5-50% of the total red cell population in patients with homozygous sickle cell anemia. Since the deformation of erythrocytes containing sickle hemoglobin is highly dependent on the concentration of hemoglobin in the deoxy conformation, any method established to enumerate the true ISC count requires the hemoglobin to be in the full oxy or liganded conformation. Because the oxygen dissociation curve for sickle erythrocytes is significantly shifted to the right, extremely high partial pressures of oxygen are required to approach full saturation. On the other hand, fully liganding the hemoglobin in the oxy conformation with carbon monoxide (CO) can be readily accomplished. We found that there is a significant reduction in the average number of sickled forms in the peripheral blood of sickle cell anemia patients after incubation in CO (to a value of 6.5 +/- 3.5%) when compared to conventional methods for ISC preparations. These results suggest that fully liganded erythrocytes should be used in quantitating ISCs in studies of the pathophysiology of this disease, especially since ISCs are likely to affect rheology differently from reversibly sickling cells.
Anemia, Sickle Cell↗
Noninvasive techniques to evaluate the vaso-occlusive manifestations of sickle cell disease.
Although the pathophysiologic manifestations of sickle cell disease have been assumed to result from microvascular occlusion consequent to in situ sickling of erythrocytes, actual blood vessel obstruction have been rarely demonstrated in vivo. Recent observations utilizing sophisticated biophysical techniques to study the intracellular hemoglobin S polymerization process has led to major revisions in this previously held pathophysiologic paradigm, but in vivo correlations are still lacking. With the development of new noninvasive imaging and para-imaging methods, it is now technically possible and feasible to characterize both regional organ perfusion and tissue biochemistry in quantitative terms. In addition, these modalities promise to clarify pathogenesis of the disease through definition of the events responsible for the progression from tissue ischemia and infarction through the resolution phase. Since these noninvasive techniques are amenable to sequential applications, they should facilitate objective evaluations of clinical trials of therapeutic agents designed to prevent or delay the vaso-occlusive manifestations of sickle cell disease.
Anemia, Sickle Cell↗
Conjunctival sign in sickle cell anaemia: an in-vivo correlate of the extent of red cell heterogeneity.
A consecutive series of 22 stable adult inpatients with sickle cell anaemia were examined for the presence and severity of spontaneous 'comma' signs of the conjunctiva. Fifteen patients had severe conjunctival signs (more than 10 commas in the worse eye). The presence of severe conjunctival signs was associated with a broader distribution of intraerythrocytic haemoglobin concentrations (p = 0.0005). The patient group with severe conjunctival signs was not found to be significantly different from the group without such signs for age, sex, haemoglobin value, reticulocyte count, alpha-globin gene number, percentage fetal haemoglobin, or the proportion of very dense cells (CHC greater than 37 g/dl). Thus the singular heterogeneity of the erythrocytes in sickle cell disease may be indicative of the factor(s) responsible for the diagnostic comma sign.
Adult↗
Alpha thalassemia changes erythrocyte heterogeneity in sickle cell disease.
Homozygous alpha-thalassemia has the beneficial effect in sickle cell anemia of reducing the hemolytic severity while changing several other hematological parameters. We examined in detail the cellular basis of some of these hematologic alterations. We find that the broad distribution in erythrocyte density and the large proportion of dense cells associated with sickle cell anemia are both reduced with coexisting alpha-thalassemia. Measurements of glycosylated hemoglobin levels as a function of cell density indicate that the accelerated increase in cell density, beyond normal cell aging, in sickle cell anemia is also reduced with alpha-thalassemia. The patients with homozygous alpha-thalassemia and sickle cell disease have slightly lower levels of hemoglobin F than the nonthalassemic sickle cell patients. Examination of hemoglobin F production revealed that the proportion of hemoglobin F containing reticulocytes remained unchanged, as did the proportion of hemoglobin F in cells containing hemoglobin F (F cells). Preferential survival of F cells occurs in sickle cell anemia, with or without alpha-thalassemia, and the slight difference in hemoglobin F levels appear to reflect differences in numbers of circulating F cells. Thus, in sickle cell disease with coexisting alpha-thalassemia, the change in the erythrocyte density profile, possibly due to inhibition of polymerization-related increases in cell density, explains the hematological improvement.
Anemia, Sickle Cell↗
Cell heterogeneity in sickle cell disease: quantitation of the erythrocyte density profile.
An increasing body of experimental evidence demonstrates that intracellular hemoglobin concentration and composition is a primary determinant of pathophysiology in sickle cell disease. To quantitate more precisely the heterogeneous distribution of intracellular hemoglobin concentrations in a given individual with this disease, we have calibrated the phthalate ester separation technique by using discontinuous Stractan density gradients to isolate subpopulations of red cells of relatively uniform corpuscular hemoglobin concentration values. We find that blood from individuals with sickle cell anemia exhibits a markedly broader distribution of corpuscular hemoglobin concentration values, containing both very light and very dense cells, than the red cell density profile from normal individuals. This increased breadth of cell densities in patients with sickle cell anemia remains even after exclusion of the very light and very dense subpopulations. In patients with stable sickle cell anemia, there appears to be minimal variation in the distribution of cell densities that are unimodal but skewed toward higher density values. The phthalate ester method can conveniently be used to follow changes in cell densities during vaso-occlusive events, to monitor therapy targeted at modifying intracellular hemoglobin S concentrations, and in sequential applications in large field trials designed to determine the relationship between red cell heterogeneity and specific manifestations of the sickle cell syndromes.
Adult↗
Periodic microcirculatory flow in patients with sickle-cell disease.
We have applied the technique of laser-Doppler velocimetry to compare patterns of cutaneous blood flow in the forearms of patients with stable sickle-cell disease, with the patterns in normal subjects matched for age, race, and sex, and in patients with anemia due to beta+-thalassemia. The mean resting blood flow in the patients with sickle-cell disease was comparable to that of the control groups but was associated with large, local oscillations in flow with periods of 7 to 10 seconds and peak-to-trough magnitudes about half the mean flow. Oscillations occurred simultaneously at sites separated by 1 cm but were independent in phase and frequency. Since these laser-Doppler measurements represent the average flow pattern in about 1 mm3 of skin (i.e., in approximately 50 to 70 capillary loops), these results suggest that microcirculatory flow in patients with sickle-cell disease proceeds by synchronization of rhythmic flow in large domains of microvessels. These findings indicate that periodic flow may be a compensatory mechanism to offset the deleterious altered rheology of erythrocytes containing polymerized hemoglobin S, and suggest that laser-Doppler velocimetry may be a useful method to investigate microvascular physiology in patients with sickle-cell disease.
Adult↗
Cryoprecipitate therapy in amniotic fluid embolization.
Cryoprecipitate was administered to a patient with severe adult respiratory distress syndrome secondary to an amniotic fluid embolus, diagnosed cytologically. Following the administration of cryoprecipitate, cardiopulmonary and hematologic status markedly improved, and the patient recovered without apparent sequela. She is the sixth surviving patient reported to have an amniotic fluid embolus confirmed cytologically. On the basis of accumulating data on the relationship between fibronectin levels and the integrity of the reticuloendothelial system, it is quite possible that fibronectin (cold-insoluble globulin), and not fibrinogen, played the key role in her dramatic improvement and may well have been responsible for the clinical improvement in earlier patients treated with blood products containing fibronectin.
Adult↗
Red blood cell glucose-6-phosphate dehydrogenase activity in aged humans.
The enzyme glucose-6-phosphate dehydrogenase (G6PD) was assayed in the circulating erythrocytes of 38 20-to 30-year-old subjects and 29 80- to 90-year-old subjects. The red blood cell G6PD activity of an aged-unbiased erythrocyte population in the young group was found to be significantly higher than in the older group (5.46 +/- 1.06) vs (4.31 +/- 0.99) (P less than 0.001), respectively (mean +/- SD). No significant difference was observed between the mean enzyme values of the male and female subjects in the two age groups. Since the mature red blood cell is devoid of regenerative capabilities, one may propose an explanation for this observation that implicates either an alteration in G6PD synthesis in the erythrocyte precursor cells in aged hosts, and/or the presence of an inhibitory factor that has the effect of decreasing the assayed activity for this enzyme.
Adult↗
Impaired deformability of Heinz body-forming red cells.
Although a decrease in the deformability of red blood cells (RBCs) has been suspected in Heinz body-forming hemolytic anemia, it remains uncertain whether the formation of Heinz bodies themselves impairs RBC deformability or not. To elucidate this question, we used RBCs treated with phenylhydrazine and RBCs from patients with unstable hemoglobin (Hb) disease (Hb Yokohama) to investigate the effect of Heinz body formation on deformability in terms of RBC filterability through nickel mesh and viscosity of the RBC suspension. The phenylhydrazine-treated RBCs exhibited a marked decrease in deformability in a dose-dependent manner. The Heinz body-forming RBCs from the patients also showed a marked decrease in deformability. Thus we confirmed that Heinz body formation impairs RBC deformability. Further, both phenylhydrazine-treated RBCs and RBCs from the patient showed a degradation of spectrin without any cross-linking of membrane proteins, thereby suggesting that the impaired deformability is associated with the oxidative degradation of the cytoskeletal framework. In summary, this study supports the conclusion that RBC deformability is impaired by the presence of Heinz bodies as well as the related oxidative damage involved in their formation.
Anemia, Hemolytic↗