Richard H. Sills

Splenic function: physiology and splenic hypofunction

A wide variety of disorders can result in diminished splenic function. The pathophysiology appears to be clearly defined in some instances, such as congenital asplenia and disorders of splenic vascular obstruction or congestion. In others, such as the autoimmune and GI disorders, the mechanism remains poorly defined. Further research is needed. The hyposplenia which occurs in many of these disorders has been associated with an increased risk of life-threatening, overwhelming bacterial sepsis. In other instances, this complication has not been reported. This certainly should not be interpreted to mean that it cannot occur. The risk of septicemia in hyposplenic disorders is rarely above 10 to 15%. In disorders with minimal inhibition of splenic function, the incidence of sepsis would presumably be less than the 1.5% incidence following surgical splenectomy for trauma. Considering these data, a very large number of patients would have to become asplenic before it would be likely that one would develop sepsis. Furthermore, the lack of awareness of the possibility of hyposplenia-related sepsis in many of these disorders may cause such occurrences to go unrecognized. Finally, since the risk of sepsis is probably less in hyposplenic adults as compared to children, studies on adults may underestimate the incidence of this complication in children. Many of the disorders reported to cause hyposplenia in adults have not been noted to do so in children. In instances such as celiac disease, it may take many years for the complication to manifest so that it would be unlikely for a child to manifest hyposplenia during childhood. However, in other instances, not enough children have been studied to be confident that the hyposplenia and its associated risk of sepsis are not complications that occur in children. Hyposplenia-related bacterial septicemia is a catastrophic complication. If a patient develops a disorder that is potentially associated with hyposplenia, the patient should be observed for signs of asplenia in the peripheral blood. If the technique is available, quantitation of red cell pits should be performed. If not, other studies of splenic function such as radionuclide scans should be considered, depending on the incidence of hyposplenia in that particular disorder. If evidence of asplenia develops, pneumococcal vaccine should be administered, penicillin prophylaxis should be considered, significant febrile episodes should be managed aggressively, and probably most importantly, the patient and family should be carefully educated about this complication. Most deaths from hyposplenia-related septicemia are preventable.

Preleukemic states in children with acute lymphoblastic leukemia

Two cases are reported of childhood acute lymphoblastic leukemia presenting with preleukemic states and 13 other cases in the literature are reviewed. Hypoplastic anemias, which transiently resolved spontaneously or with steroid therapy, were seen most commonly. Acquired hypoplastic anemias, even when associated with spontaneous resolution, may at times represent a preleukemic state.

Nephrotic Syndrome: Increased Platelet Prostaglandin Endoperoxide Formation, Hyperaggregability, and Reduced Platelet Life Span. Reversal following Remission

Summary: Nephrotic syndrome is associated with an increased incidence of arterial and venous thrombosis. Platelet function was evaluated in 6 children with active disease (group I) and in 5 children in remission (group II). Platelet malonyldialdchyde in the presence of N-ethyl maleimide (1 mM) or thromhin (0.5 unit/ml) was used as an indicator of platelet prostaglandin endoperoxide formation in all patients evaluated, and platelet survivals were performed in 3 of 11. Platelet hyperaggregability was present in group 1 and was associated with a significant increase (P < O.001) in platelet MDA formation in the presence of either N-ethyl maleimide [4.0 ± 0.29 (1 S.D.) nmoles/109 platelets] or thrombin (1.77 ± 0.32) when compared to normal controls (3.20 ± 0.26: 1.26 ± 0.18). Other evidence for a “hypercoagulable” state included a marked reduction (P < 0.001) in plasma antithrombin III levels to 9.4 ± 3.8 mg/dl (controls, 24 ± 3) and a reduction in platelet life span in both children in whom this study was performed (half-life of 2.1 and 2.5 days), Group II patients in remission did not demonstrate platelet hyperaggregability. and platelet malonyldialdehyde was normal (3.21 ± 0.4; 1.13 ± 0.19). Antithrombin III levels were normal (26.5 ± 4.8), and platelet life-span was normal in both (iroup II children in whom this parameter was measured (half-life of 3.6 and 4.4 days). The normal half-life of 4.4 days was obtained in the same child in whom a half-life of 2.5 days was present during active disease. Platelet hyperaggregability in this syndrome appears to be due to increased prostaglandin endoperoxide synthesis. Inasmuch as a reduction in plasma antithrombin HI levels predisposes to thrombosis and a decrease in platelet survival has been documented to increase the risk of (hromboembolism in a number of pathologic states, these findings appear to be of importance in the etiology of hypercoagulability associated with nephrotic syndrome.Speculation: Platelet hyperaggregability and increased prostaglandin endoperoxide formation is seen in the nephrotic syndrome during disease activity. This platelet hyperfunctional state does not appear to be solely due to concomitant hypoalbuminemia. Other possible factors include a young, reactive platelet population with enhanced functional and thrombogenic potential or the presence of hypercholesterolemia which can he associated with platelet hyperaggregability (25).Antiplatelet aggregating agents have been used therapeutically in various disease states associated with a shortened platelet life span and an increased risk of thromboembolic complications. These agents may prove to be beneficial in decreasing the incidence of thromboembolic disease in children with the nephrotic syndrome.

Formation of intracellular vesicles in neonatal and adult erythrocytes: evidence against the concept of neonatal hyposplenism

ABSTRACT: Intraerythrocytic vesicles accumulate in the peripheral blood as a result of impaired clearance of these intracellular inclusions by the spleen. The observation that neonates demonstrate an increased percentage of erythrocytes containing these vesicles constitutes the primary evidence supporting the concept that the newborn is functionally hyposplenic. Neonatal erythrocytes also demonstrate an increased propensity to undergo a variety of endocytic processes. We therefore questioned whether the increase in red cell vesicles in the neonate might be the result of increased vesicle formation as opposed to impaired splenic clearance. Newborn and adult erythrocytes were incubated in vitro in synthetic medium at 37° C. Several parameters confirmed the maintenance of physiologic conditions, including levels of erythrocyte phosphate metabolites monitored by nuclear magnetic resonance. The acquisition of intraerythrocytic vesicles during the course of these incubations was compared. Over a period of 144 h, 19.2% of neonatal erythrocytes acquired vesicles compared to 3.7% of the adult cells (p < 0.001). The increase in vesicles was greater in younger density-separated erythrocytes in both the neonate (37.6%, p < 0.0005) and the adult (10.3%, p < 0.002), but persisted even in the oldest erythrocytes (12.2% and 2.4%, respectively). We conclude that the increase in erythrocytic vesicles in the neonate may not simply be an indication of hyposplenism, but a reflection of increased vesicle formation which overwhelms the clearance capability of the spleen.

Functional Somatic Symptoms in Pediatric Hematology and Oncology

Functional somatic symptoms (FSS) in pediatric hematology and oncology significantly limit health-related quality of life and functional abilities, thus requiring regular assessment and treatment. This chapter focuses on FSS in pediatric sickle cell disease and pediatric cancer, diseases for which there is an established literature describing and explaining functional abilities, health-related quality of life, and other adaptive outcomes. Pain and fatigue in pediatric sickle cell disease and pain, nausea, vomiting, and fatigue in pediatric cancer are among the most common and distressing disease and treatment complications. Although physical in etiology, psychosocial risks and resources across multiple levels of pediatric patients’ social ecology influence the frequency, intensity, and course of these FSS. The literature regarding common approaches to assessment of pain, anticipatory nausea and vomiting, and fatigue as well as associated risk factors is summarized. Use of self- and parent proxy report measures of FSS, internalizing and externalizing symptoms, and psychosocial risk screening are recommended. Case studies demonstrate differential diagnosis and application of medical- and evidence-based psychological interventions for FSS. Importantly, multidisciplinary care models for pediatric sickle cell disease and pediatric cancer are consistent with the recommended approach to FSS.

873 EFFECTS OF PHOSPHODIESTERASE INHIBITORS (PI) UPON THE DEFORMABILITY OF SICKLE CELLS

We studied the in vitro effect of 3 Pis upon the deformability of red cells (RCD) from patients with homozygous sickle cell disease (SSD). The subjects were clinically stable and had not been transfused. The RCD was quantitated by measuring the filtration time (FT) of a red cell suspension through polycarbonate filters under aerobic conditions. Venous samples were incubated with one of 3 Pis (RA233 .12 mg/cc, pentoxifylline .18 mg/cc, aminophylline .1 and .02 mg/cc) and alone as a control. FTs were measured after 30 and 60 minutes of incubation. RA233 treated cells from 6 patients exhibited FTs of 190.6±86.3 secs at 30 min and 190±109.9 at 60 min versus control values of 274.6±131.3 and 323.5±119.5 respectively. These differences are significant (P < 0.05 & P < 0.005). The improvement at 30 versus 60 min with RA233 was not significantly different. Pentoxifylline and the 2 concentrations of aminophylline were each studied in 6 patients. All samples exhibited improved FTs but this did not attain statistical significance with these small groups. Six normal patients did not exhibit a significant change in FT with RA233.RA233, a PI, improves the deformability of oxygenated sickle cells in vitro. The mechanism of this alteration is not known. Further in vitro studies of RA233 and the other PIs are indicated to justify clinical trials of these agents in the prevention of the vasoocclusive symptoms of SSD.

872 DECREASED RED CELL DEFORMABILITY (RCD) IN BACTERIAL MENINGITIS

Haemophilus influenzae meningitis has been associated with anemia. Although the mechanism of this anemia has not been investigated, accelerated red cell destruction has been assumed because of the rapid decrease in hemoglobin in the absence of bleeding. To further define this pathophysiology, the RCD of patients with meningitis was studied by measuring the filtration time of washed red cells through polycarbonate filters. Eleven patients with Haemophilus influenzae meningitis, 3 with meningococcal meningitis, 9 with aseptic meningitis and 30 normal children were studied. The filtration time of the Haemophilus influenzae meningitis group (81.2 ± 96.1 secs) was significantly prolonged (P < 0.01) compared to the aseptic group (24.7 ± 6.4) and a group of normals (24.1 ± 5.3). The 3 children with meningococcal meningitis had filtration times of 73.5, 18.7 and 34.9 secs. Only 3 of 11 Haemophilus influenzae meningitis subjects fell within the normal range. Nine of 14 patients with bacterial meningitis were anemic versus 1/9 in the aseptic group.This study demonstrates that RCD is significantly diminished in children with bacterial meningitis. This decreased deformability may result in a diminished red cell survival and account for the postulated hemolytic anemia associated with this illness. The mechanism by which the RCD is altered remains to be elucidated.

658 DIRECT INTEEFEKENCE CONTRAST MICROSCOPY (DICK) AS A MEASUREMENT OF SPLENIC FUNCTION

The presence of red blood cell (RBC) membrane surface “pits” as revealed by DICM has been demonstrated to connote splenic hypofunction. DICM was employed to study splenic function in a variety of pediatric disorders and to compare its sensitivity with that of Howell-Jolly body (HJB) counts. Normal adults exhibited pitting on 0.70±0.82% of their RBCs as compared to 0.90±0.71% for infants and children 6-108 mos. of age. In 14 pts. without spleens the mean pit count was 38.7±12.6%. In 6 children with sickle cell anemia (SS) ages 7 mos. to 16 yrs., the pit count averaged 35.8%. A 7 mo. old with SS and 22.5% pitting was hypertransfused over 2 wks. and his % pitting fell to normal within 1 wk. and remained there for 3 mos. This documents the presence and reversibility of splenic hypofunction in young SS pts. A pt. with S-C disease and one with S-thalassemia also exhibited splenic hypofunction (48.4 & 54.6% pits respectively). 5 newborns with sepsis and 5 children with sepsis &/or meningitis were evaluated as to the possible role of hyposplenism in septicemia. No abnormality in RBC pitting was noted. DICM was compared to the presence of HJB from peripheral smears. No pt. had HJB without an elevated pit count. Surface pits always preceded the appearance of HJB in splenectomized pts. In 32 samples with elevated pit counts, 7 had no HJB. These data indicate that the use of DICM for detection of surface “pits” is a rapid and sensitive technique for the detection of splenic hypofunction and is superior to the use of HJB counting.

L-ASPARAGINASE |[lpar]|L-ASP|[rpar]| INDUCED COAGULATION ABNORMALITIES

Clotting abnormalities can occur with L-Asp therapy. During routine monitoring of coagulation studies in 7 consecutive patients with acute lymphocvtic leukemia receiving L-Asp IV (1000 μ/Kg/da × 10 d) a prolonged PTT was noted in all. In order to determine the frequency of specific clotting abnormalities, 5 of these patients were studied more thoroughly. The PT was normal in all. The thrombin time was prolonged in 3/5 subjects. The fibrinogen level was abnormal in 4/5, but never fell to less than 100 mg%. Fibrin split products were not detected in any subject. Factors XII, XI, X, VII and V remained normal while F-VIII demonstrated occasional inconsistent abnormalities. In all patients, depressed levels of F-IX occurred with the minimum levels ranging from 11 to 19%. No F-IX inhibitors were found. The low F-IX levels remained low until the drug was discontinued, then promptly returned to normal in 4-7 days. In several patients, the drug was continued in spite of the clotting defect and clinical bleeding manifestations did not occur. Liver function tests were normal in all. The coagulation abnormalities were observed with 3 different lots of L-Asp. These findings indicate a pattern of coagulation abnormalities not previously noted: specifically that the most frequently occurring disturbance is depression of F-IX levels which was observed uniformly in all subjects studied prospectively.