Bleeding diathesis and gastro-duodenal ulcers in inherited cytosolic phospholipase-A2 alpha deficiency

Elena M. Faioni; Cristina Razzari; Aida Zulueta; Eti A. Femia; Lara Fenu; Marco Trinchera; Gian Marco Podda; Mariateresa Pugliano; Francesco Marongiu; Marco Cattaneo

doi:10.1160/th14-04-0352

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 112(06): 1182-1189
DOI: 10.1160/th14-04-0352

Platelets and Blood Cells

Schattauer GmbH

Bleeding diathesis and gastro-duodenal ulcers in inherited cytosolic phospholipase-A2 alpha deficiency

Authors

Elena M. Faioni

¹Medicina 3, Azienda Ospedaliera San Paolo and Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy
Cristina Razzari

¹Medicina 3, Azienda Ospedaliera San Paolo and Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy
Aida Zulueta

²Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy
Eti A. Femia

¹Medicina 3, Azienda Ospedaliera San Paolo and Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy
Lara Fenu

³Dipartimento di Scienze Mediche Internistiche, Università di Cagliari, Cagliari, Italy
Marco Trinchera

⁴Dipartimento di Medicina Clinica e Sperimentale, Università dell’Insubria, Varese; Italy
Gian Marco Podda

¹Medicina 3, Azienda Ospedaliera San Paolo and Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy
Mariateresa Pugliano

¹Medicina 3, Azienda Ospedaliera San Paolo and Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy
Francesco Marongiu

³Dipartimento di Scienze Mediche Internistiche, Università di Cagliari, Cagliari, Italy
Marco Cattaneo

¹Medicina 3, Azienda Ospedaliera San Paolo and Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy

Abstract

Summary

Arachidonic acid (AA), when cleaved from phospholipids by cytosolic phospholipase A2 alpha (cPLA2a), generates eicosanoids, with pro-hemostatic, pro-inflammatory, vasoactive and gastro-protective functions. We describe a patient (27-year-old man) and his twin-sister with early-onset bleeding diathesis and recurrent gastro-intestinal (GI) ulcers. Platelet aggregation/δ-granules secretion by collagen was impaired, but normal by AA; serum levels of thromboxane (Tx) B₂ and 12-hydroxyeicosatetraenoic acid, and urinary levels of 11-dehydro- TxB₂ were extremely low. Patients were homozygous for 1723G>C transition in PLA2G4A gene, which changed the codon for Asp575 to His. GI ulcers affected 5/14 heterozygous (< 40 years) and 1/16 wildtype homozygous (> 60 years) family members; none had bleeding diathesis. The proband, his sister and mother also had mildly reduced factor XI levels. Platelet messenger RNA expression did not differ among subjects with different PLA2G4A genotypes. Conversely, platelet cPLA2a was undetectable by Western Blotting in the proband and his sister, and decreased in 1723G>C heterozygous subjects, suggesting that the variant is transcribed, but not translated or translated into an unstable protein. We described a syndromic form of deficiency of cPLA2a , characterised by recurrent GI ulcers and bleeding diathesis, associated with mild inherited deficiency of factor XI. Unlike other reported patients with cPLA2a deficiency, these patients had extremely low levels of platelet TxA₂ biosynthesis.

Keywords

Platelet function disorders - bleeding diathesis - phospholipase A2a deficiency - eicosanoids - gastro-duodenal ulcers

Full Text

References

References
1 Harizi H, Corcuff JB, Gualde N. Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology. Trends Mol Med 2008; 14: 461-469.
2 Niknami M, Patel M, Witting PK. et al. Molecules in focus: cytosolic phospholipase A2-alpha. Int J Biochem Cell Biol 2009; 41: 994-997.
3 Dennis EA, Cao J, Hsu YH. et al. Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem Rev 2011; 111: 6130-6185.
4 Mustard JF, Kinlough-Rathbone RL, Packham MA. Prostaglandins and platelets. Annu Rev Med 1980; 31: 89-96.
5 Podda G, Femia EA, Pugliano M. et al. Congenital defects of platelet function. Platelets 2012; 23: 552-563.
6 Patrono C, Garcí a Rodríguez LA, Landolfi R. et al. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353: 2373-2383.
7 Atay S, Tarnawski AS, Dubois A. Eicosanoids and the stomach. Prostaglandins Other Lipid Mediat 2000; 61: 105-124.
8 Tarnawski A, Erickson RA. Sucralfate, 24 years later: current concepts of its protective and therapeutic actions. Europ J Gastroenterol Hepatol 1991; 03: 795-810.
9 Redfern JS, Feldman M. Role of endogenous prostaglandins in preventing gastrointestinal ulceration: induction of ulcers by antibodies to prostaglandins. Gastroenterology 1989; 96: 596-605.
10 Rodeghiero F, Tosetto A, Abshire T. et al. ISTH/SSC joint VWF and Perinatal/ Pediatric Haemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 08: 2063-2065.
11 Cattaneo M. Light transmission aggregometry and ATP release for the diagnostic assessment of platelet function. Semin Thromb Haemost 2009; 35: 158-167.
12 Femia EA, Pugliano M, Podda G. et al. Comparison of different procedures to prepare platelet-rich plasma for studies of platelet aggregation by light transmission aggregometry. Platelets 2012; 23: 7-10.
13 Cattaneo M, Cerletti C, Harrison P. et al. Recommendations for the Standard-isation of Light Transmission Aggregometry: A Consensus of the Working Party from the Platelet Physiology Subcommittee of SSC/ISTH. J Thromb Haemost 2013; 11: 1183-1189.
14 Cattaneo M, Lecchi A, Zighetti ML. et al. Platelet aggregation studies: autologous platelet-poor plasma inhibits platelet aggregation when added to platelet-rich plasma to normalize platelet count. Haematologica 2007; 92: 694-697.
15 Zarini S, Gijón MA, Ransome AE. et al. Transcellular biosynthesis of cysteinyl leukotrienes In Vivo during mouse peritoneal inflammation. Proc Natl Acad Sci USA 2009; 106: 8296-8301.
16 Ciabattoni G, Maclouf J, Catella F. et al. Radioimmunoassay of 11-dehydrothromboxane B2 in human plasma and urine. Biochim Biophys Acta 1987; 918: 293-297.
17 Mare L, Trinchera M. Comparative analysis of retroviral and native promoters driving expression of beta1,3-galactosyltransferase beta3Gal-T5 in human and mouse tissues. J Biol Chem 2007; 282: 49-57.
18 Caretti A, Sirchia SM, Tabano S. et al. DNA methylation and histone modifications modulate the 1,3 galactosyltransferase 3Gal-T5 native promoter in cancer cells. Int J Biochem Cell Biol 2012; 44: 84-90.
19 Gilliland G, Perrin S, Blanchard K. et al. Analysis of cytokine mRNA and DNA: detection and quantitation by competitive polymerase chain reaction. Proc Natl Acad Sci USA 1990; 87: 2725-2729.
20 Mannucci PM, Vicente V, Vianello L. et al. Controlled trial of desmopressin in liver cirrhosis and other conditions associated with a prolonged bleeding time. Blood 1986; 67: 1148-1153.
21 Podda GM, Bucciarelli P, Lussana F. et al. Usefulness of PFA-100 testing in the diagnostic screening of patients with suspected abnormalities of haemostasis: comparison with the bleeding time. J Thromb Haemost 2007; 05: 2393-2398.
22 Dolan-O’Keefe M, Chow V Monnier J. et al. Transcriptional regulation and structural organisation of the human cytosolic phospholipase A2 gene. Am J Physiol Lung Cell Mol Physiol 2000; 278: L649-L657.
23 Patrono C, Baigent C. Low-dose aspirin, coxibs, and other NSAIDS: a clinical mosaic emerges. Mol Interv 2009; 09: 31-39.
24 Adler DH, Cogan JD, Phillips JA. et al. Inherited human cPLA(2alpha) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction. J Clin Invest 2008; 118: 2121-2131.
25 Reed KA, Tucker DE, Aloulou A. et al. Functional characterisation of mutations in inherited human cPLA[two.inferior] deficiency. Biochemistry 2011; 50: 1731-1738.
26 Brooke MA, Longhurst HJ, Plagnol V. et al. Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2- . Gut 2014; 63: 96-104.
27 Kitchens CS. Factor XI: A review of its biochemistry and deficiency. Sem Thromb Haemost 1991; 17: 55-72.
28 Kaneshiro MM, Mielke Jr CH, Kasper CK. et al. Bleeding time after aspirin in disorders of intrinsic clotting. N Engl J Med 1969; 281: 1039-1042.
29 Rao GH, Johnson GJ, White JG. Influence of epinephrine on the aggregation response of aspirin-treated platelets. Prostaglandins Med 1980; 05: 45-58.
30 Moscardó A, Santos MT, Fuset MP. et al. Residual cyclooxygenase-1 activity and epinephrine reduce the antiplatelet effect of aspirin in patients with acute myocardial infarction. Thromb Haemost 2011; 105: 663-669.
31 John R, Herzenberg AM. Renal toxicity of therapeutic drugs. J Clin Pathol 2009; 62: 505-515.
32 Hao CM, Breyer MD. Physiological regulation of prostaglandins in the kidney. Annu Rev Physiol 2008; 70: 357-377.
33 Downey P, Sapirstein A, O’Leary E. et al. Renal concentrating defect in mice lacking group IV cytosolic phospholipase A(2). Am J Physiol Renal Physiol 2001; 280: F607-618.