Wiskott-Aldrich Syndrome: Detection of Carrier State by Metabolic Stress of Platelets

Shapiro, R. S.; Perry, GuyS.; Krivit, William; Gerrard, Jonathan M.; Jg, White; Kersey, JH

doi:10.1016/s0140-6736(78)90419-1

Cited by 29 publications

(9 citation statements)

References 15 publications

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“…The defective aggregation to these aggregating agents is identical to that found in either storage pool deficient platelets (Holmsen & Weiss, 1970;White et al, 1971) or in platelets with absent cyclo-oxygenase activity due to aspirin treatment (Weiss et a!, 1968), or in patients in which metabolic ATP has been depleted (Shapiro et al, 1978). Collagen aggregation was also often abnormal.…”

Section: Discussionmentioning

confidence: 99%

“…Collagen aggregation was also often abnormal. The defective aggregation to these aggregating agents is identical to that found in either storage pool deficient platelets (Holmsen & Weiss, 1970;White et al, 1971) or in platelets with absent cyclo-oxygenase activity due to aspirin treatment (Weiss et a!, 1968), or in patients in which metabolic ATP has been depleted (Shapiro et al, 1978). It was therefore essential to distinguish between these three abnormalities in CML platelets and to rule out additional possibilities such as a defect in phospholipase A2 activity or the presence of an inhibitor which might produce a similar aggregation pattern.…”

Section: Discussionmentioning

confidence: 99%

“…Platelets are one of the cell lines involved in chronic granulocytic leukaemia (CGL) as shown by the presence of the Philadelphia chromsome in megakaryocytes (Tough et al, 1963). Abnormalities of platelet function have been found in CGL (Perry, 1957;Sultan et all 1969;Sultan & Jeanneau, 1971;Tangiin, 1971;Inceman & Tangiin, 1972;Neemah et al, 1972;Cardamone et al, 1972;Adams et al, 1974;Cowan et all 1975;Ulutin, 1976;Keenan et all 1977).…”

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Platelet Storage Pool Deficiency and Prostaglandin Synthesis in Chronic Granulocytic Leukaemia

et al. 1978

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Platelet function was evaluated in eight patients with chronic granulocytic leukaemia (CGL), seven Ph1 positive and one Ph1 negative. Seven of the eight patients' platelets had an absence of the second wave of adrenaline induced aggregation on at least one occasion, while five had impaired collagen aggregation. The platelets of all seven patients with abnormal responses to adrenaline, aggregated with arachidonic acid, thus ruling out a cyclo-oxygenase deficiency. A marked decrease in the ADP, serotonin, and dense body content of platelets was found in all five patients evaluated. Mixtures of CGL patient platelets with platelets from normal donors who had ingested aspirin gave a normal biphasic response to adrenaline. Normal release of the storage pool contents from aspirin treated platelets was shown by stirring a mixture of CGL platelets and 14C-serotonin labelled aspirin treated platelets with adrenaline. The CGL platelets alone or in the mixture produced malondialdehyde in response to adrenaline. These experimental results suggest that CGL platelets have a storage pool deficiency but can synthesize prostaglandins and thromboxanes in response to arachidonic acid and adrenaline.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Platelet Storage Pool Deficiency and Prostaglandin Synthesis in Chronic Granulocytic Leukaemia

et al. 1978

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“…This correlation has been most strikingly demonstrated in erythrocytes, in which a variety of hemolytic anemias have been correlated with inherited disorders of glycolysis (17). More recent data suggest that the defect in platelets of patients with Wiskott-Aldrich Syndrome may be related to an inborn error of the Krebs Cycle (14).…”

Section: Speculationmentioning

confidence: 95%

Glucose Metabolism of Human Mononuclear Cell Subpopulations

Storch¹,

Klein²,

Feig³

et al. 1980

Pediatr Res

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SummaryPrevious studies have demonstrated metabolic dysfunction in the mononuclear cells of some children with abnormal cell-mediated immunity. Interpretation of these observations has been complicated by the extreme heterogeneity of cell types examined. The glycolytic metabolism of relatively enriched T-cells, non-T mononuclear cells (NTM), non-T lymphocytes (NTL), and monocytes was studied in an attempt to measure the metabolism of subpopulations of mononuclear cells.Lactate production by monocytes was 11 times greater than that of T-cells and 2% times greater than that of non-T lymphocytes. Exposure to phytohemagglutinin (PHA) stimulated glycolytic metabolism in T-cells but did not stimulate glucose utilization or lactate production in NTM. Even when T-cells were maximally stimulated by PHA, their observed metabolism was still lower than that of NTL. The ATP content of T lymphocytes and NTL was similar and was constant under the conditions of incubation. The initial ATP content of monocytes was higher than that of lymphocytes, and diminished during incubation.Tricarboxylic acid cycle activity did not contribute significantly to ATP synthesis in any of the mononuclear cell subpopulations, under the conditions of incubation used in this study. Significant hexose monophosphate shunt activity was observed in all mononuclear cell types.These studies demonstrate major metabolic differences between mononuclear cell subtypes. Any correlation of metabolic observation with clinical dysfunction of mononuclear cells requires the study of relatively pure cell populations. SpeculationThe reason for increased glycolysis in NTL is obscure. It may imply an immaturity of a portion of those cells, by analogy to the increased glycolytic activity of young erythrocytes. Alternatively, a subset of NTL may require increased ATP synthesis to perform its functions. In order to delineate these possibilities, methods must be developed which will allow the isolation of large numbers of B and Null lymphocytes for metabolic and functional studies.The performance of biologic functions by cells requires the expenditure of energy derived from cellular metabolism. Cellular dysfunction can be correlated with perturbations of energy metabolism by the dysfunctional cell. This correlation has been most strikingly demonstrated in erythrocytes, in which a variety of hemolytic anemias have been correlated with inherited disorders of glycolysis (17). More recent data suggest that the defect in platelets of patients with Wiskott-Aldrich Syndrome may be related to an inborn error of the Krebs Cycle (14).The authors postulated that malfunction of human mononuclear leukocytes might be caused by or associated with disorders of energy metabolism. Several models of cell-mediated immune dysfunction were studied and diminished ATP content in the mononuclear cells of newborn infants (5) and patients with severe malnutrition (4) have been described. Spec*c correlation between a metabolic deficit and a cellular malfunction could not be made because of the heterog...

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confidence: 99%

The Wiskott‐Aldrich syndrome: studies on a possible defect in mitochondrial ATP resynthesis in platelets

Akkerman¹,

Brederode²,

Gorier³

et al. 1982

Br J Haematol

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A possible defect in mitochondrial ATP resynthesis in platelets has been used for detection of Wiskott-Aldrich syndrome carriers (Shapiro et al, 1978). The detection was based on an abnormal adrenaline-induced platelet aggregation under conditions that only the mitochondria provide metabolic energy. We evaluated the test and found false negative and false positive results which raised doubts about the applicability of the test and the nature of the underlying defect. Direct analysis of mitochondrial ATP regeneration in patients and carriers showed an impaired mitochondrial energy production which was insufficient to maintain ATP homeostasis when glycolytic energy production was inhibited. Also abnormal was the fall in metabolic ATP concentration during stimulation with adrenaline and especially with thrombin when the platelets were incubated in glucose-free medium. These data provide direct evidence for a regulation defect in mitochondrial ATP resynthesis in platelets of patients and carriers with Wiskott-Aldrich syndrome.

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Wiskott-Aldrich Syndrome: Detection of Carrier State by Metabolic Stress of Platelets

Cited by 29 publications

References 15 publications

Platelet Storage Pool Deficiency and Prostaglandin Synthesis in Chronic Granulocytic Leukaemia

Platelet Storage Pool Deficiency and Prostaglandin Synthesis in Chronic Granulocytic Leukaemia

Glucose Metabolism of Human Mononuclear Cell Subpopulations

The Wiskott‐Aldrich syndrome: studies on a possible defect in mitochondrial ATP resynthesis in platelets

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