Acquired immune-mediated thrombophilia in lymphoproliferative disorders

Leukemia and Lymphoma

Volumn 52, Issue 10, 2011, Pages 1836-1843

  Lechner, Klaus ^a   Simonitsch, Ingrid ^a   Haselböck, Johanna ^a   Jger, Ulrich ^a   Pabinger, Ingrid ^a  

^a MEDICAL UNIVERSITY OF VIENNA   (Austria)

Author keywords

lupus anticoagulant; lymphoma; paraneoplastic; Thrombophilia

Indexed keywords

IMMUNOGLOBULIN G; IMMUNOGLOBULIN M; LUPUS ANTICOAGULANT; PHOSPHOLIPID ANTIBODY; PROTEIN ANTIBODY; PROTEIN C ANTIBODY; PROTEIN S ANTIBODY; UNCLASSIFIED DRUG; VON WILLEBRAND FACTOR CLEAVING PROTEINASE;

ANGIOIMMUNOBLASTIC T CELL LYMPHOMA; ANTIPHOSPHOLIPID SYNDROME; ARTERY THROMBOSIS; AUTOIMMUNE HEMOLYTIC ANEMIA; AUTOIMMUNE THROMBOCYTOPENIA; FOLLICULAR LYMPHOMA; HAIRY CELL LEUKEMIA; HODGKIN DISEASE; HUMAN; IMMUNOTHERAPY; LARGE CELL LYMPHOMA; LYMPHOMA; LYMPHOPLASMACYTIC LYMPHOMA; LYMPHOPROLIFERATIVE DISEASE; MANTLE CELL LYMPHOMA; MUCOSA ASSOCIATED LYMPHOID TISSUE LYMPHOMA; MYELOMA; NONHODGKIN LYMPHOMA; PARAPROTEINEMIA; PRIORITY JOURNAL; REVIEW; SPLENECTOMY; SPLENIC MARGINAL ZONE LYMPHOMA; T CELL LYMPHOMA; THROMBOPHILIA; VENOUS THROMBOEMBOLISM;

ADAM PROTEINS; AUTOANTIBODIES; HUMANS; LUPUS COAGULATION INHIBITOR; LYMPHOMA; LYMPHOPROLIFERATIVE DISORDERS; PROTEIN C; PROTEIN S; THROMBOPHILIA;

EID: 80053182194     PISSN: 10428194     EISSN: 10292403     Source Type: Journal    
DOI: 10.3109/10428194.2011.580474     Document Type: Review

References (97)

1. Mohren M, Markmann I, Jentsch-Ullrich K, Koenigsmann M, Lutze G, Franke A. Increased risk of thromboembolism in patients with malignant lymphoma: a single-centre analysis. Br J Cancer 2005;92:1349-1351. (Pubitemid 40704998)
2. Ottinger H, Belka C, Kozole G, et al. Deep venous thrombosis and pulmonary artery embolism in high-grade non Hodgkin's lymphoma: incidence, causes and prognostic relevance. Eur J Haematol 1995;54:186-194.
3. Brandt JT, Barna LK, Triplett DA. Laboratory identification of lupus anticoagulants: results of the Second International Workshop for Identification of Lupus Anticoagulants. On behalf of the Subcommittee on Lupus Anticoagulants/Antiphospholipid Antibodies of the ISTH. Thromb Haemost 1995;74:1597-1603. (Pubitemid 26018092)
4. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306.
5. Pengo V, Tripodi A, Reber G. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009;7: 1737-1740.
6. Asherson RA. The catastrophic antiphospholipid (Asherson's) syndrome. Autoimmun Rev 2006;6:64-67.
7. Brohée D, Delval L, Cauchie P. CD4 lymphocyte deficiency and non-Hodgkin's lymphoma in the antiphospholipid syndrome. Ann Oncol 1998;9:921. (Pubitemid 28440454)
8. Davidson SJ, Burman JF, Nicholson AG, Jones DW, Dusmet ME. Factor XII auto-antibodies present in a patient with a B-cell lymphoma. Blood Coagul Fibrinolysis 2005;16:365-367. (Pubitemid 41008744)
9. Erre GL, Pardini S, Faedda R, Passiu G. Effect of rituximab on clinical and laboratory features of antiphospholipid syndrome: a case report and a review of literature. Lupus 2008;17:50-55. (Pubitemid 351487020)
10. Liozon E, Loustaud V, Jauberteau MO, et al. Non-simultaneous malignant lymphoma and antiphospholipid syndrome: 4 cases. Rev Med Interne 2001;22:360-370. (Pubitemid 32303707)
11. Keung YK, Cobos E, Meyerrose GE, Roberson GH. Progressive thrombosis after treatment of diffuse large cell non-Hodgkin's lymphoma and concomitant lupus anticoagulant. Leuk Lymphoma 1996;20:341-345. (Pubitemid 126714891)
12. Mills RC, Zacharski LR, McIntyre OR. Case report: circulating anticoagulant, autoimmune hemolytic anemia and malignant lymphoma. Am J Med Sci 1977;274:75-81.
13. Shaw BE, Perry D, Hoffbrand AV. Progressive arterial thrombosis in a patient with non-Hodgkin's lymphoma, a lupus anticoagulant, factor V Leiden mutation and paraprotein, following chemotherapy. Leuk Lymphoma 2001;42:221-223. (Pubitemid 32700940)
14. Stefani PM, Pietrogrande F, Sartori R, Girolami A. Immunosuppression due to MACOP-B does not seem to cure the antiphospholipid syndrome. Haematologica 1999;84: 751-752. (Pubitemid 29424415)
15. Zuber M, Gherardi R, Defer G, Gaulard P, Divine M, Zafrani ES. Peripheral neuropathy, coagulopathy and nodular regenerative hyperplasia of the liver in a patient with multiple serologic auto-antibody activities and IgM B-cell lymphoma. J Intern Med 1989;226:291-295. (Pubitemid 19269630)
16. Kawahara M, Kanno M, Matsumoto M, Nakamura S, Fujimura Y, Ueno S. Diffuse neurodeficits in intravascular lymphomatosis with ADAMTS13 inhibitor. Neurology 2004;63:1731-1733. (Pubitemid 39507604)
17. Rodriguez M, Ancochea J, De Buen C, Merino JL, Marqués G, Vivanco F. Acquired C1-inhibitor deficiency associated with a lupus-like anticoagulant activity. Ann Allergy 1988;61: 348-350. (Pubitemid 19010077)
18. Houbouyan L, Soria J, Soria C, Goguel A. Analysis of an autoimmune antibody (IgM class) in a case of chronic lymphocytic leukaemia. Haemostasis 1974;3:171-182.
19. Cooper MR, Cohen HJ, Huntley CC, Waite BM, Spees L, Spurr CL. A monoclonal IgM with antibodylike specificity for phospholipids in a patient with lymphoma. Blood 1974;43: 493-504.
20. Bellotti V, Gamba G, Merlini G, et al. Study of three patients with monoclonal gammopathies and 'lupus-like' anticoagulants. Br J Haematol 1989;73:221-227. (Pubitemid 19256116)
21. Ikeda K, Shichishima T, Yui T, et al. B-cell chronic lymphocytic leukemia is complicated by autoimmune hemolytic anemia and anti-phospholipid syndrome. J Clin Exp Hematopathol 2002;42:75-79.
22. Vukelja SJ, Krishnan J, Link CM, Salvado AJ, Knight RD. Resolution of pure red cell aplasia and lymphoma: response to intravenous gammaglobulin and combination chemotherapy. Am J Hematol 1989;32:129-133. (Pubitemid 19218216)
23. Miljić P, Milosević-Jovicić N, Antunović P, Bosković D, Basara N, Rolović Z. Recurrent venous thrombosis in a patient with chronic lymphocytic leukemia and acquired protein S deficiency. Haematologia (Budap) 2000;30:51-54.
24. Ciaudo M, Horellou MH, Audouin J, De Carbonnieres C, Conard J, Samama M. Lupus anticoagulant associated with primary malignant lymphoplasmacytic lymphoma of the spleen: a report of four patients. Am J Hematol 1991;38: 271-276.
25. Conley CL, Savarese DM. Biologic false-positive serologic tests for syphilis and other serologic abnormalities in autoimmune hemolytic anemia and thrombocytopenic purpura. Medicine (Baltimore) 1989;68:67-84. (Pubitemid 19088083)
26. Delmer A, Garban F, Le Tourneau A, et al. Waldenström's macroglobulinemia with prominent splenomegaly and multiple immune disorders. Haematologica 1993;78: 408-410. (Pubitemid 24071676)
27. Drusin LM, Litwin SD, Armstrong D, Webster BP. Waldenström's macroglobulinemia in a patient with a chronic biologic false-positive serologic test for syphilis. Am J Med 1974;56: 429-432.
28. Dührsen U, Paar D, Kö lbel C, et al. Lupus anticoagulant associated syndrome in benign and malignant systemic disease-analysis of ten observations. Klin Wochenschr 1987; 65:852-859.
29. Gallart T, Benito C, Reverter JC, et al. True anti-anionic phospholipids immunoglobulin M antibodies can exert lupus anticoagulant activity. Br J Haematol 2002;116: 875-886. (Pubitemid 34227010)
30. Pruzanski W, Warren RE, Goldie JH, Katz A. Malabsorption syndrome with infiltration of the intestinal wall by extracellular monoclonal macroglobulin. Am J Med 1973;54:811-818.
31. Tait RC, Oogarah PK, Houghton JB, Farrand SE, Haeney MR. Waldenström's macroglobulinaemia secreting a paraprotein with lupus anticoagulant activity: possible association with gastrointestinal tract disease and malabsorption. J Clin Pathol 1993;46:678-680. (Pubitemid 23231830)
32. Wisløff F, Michaelsen TE, Godal HC. Monoclonal IgM with lupus anticoagulant activity in a case of Waldenström's macroglobulinaemia. Eur J Haematol 1987;38:456-460. (Pubitemid 17133230)
33. von Landenberg P, Schö lmerich J, Andreesen R, Vogelhuber M, Lackner KJ. A case of Waldenstroem's disease with a monoclonal IgM antiphospholipid antibody. Rheumatol Int 2002;22:129-131. (Pubitemid 34983832)
34. Abramson JS, Chatterji M, Rahemtullah A. Case records of the Massachusetts General Hospital.Case 39-2008. A 51-yearold woman with splenomegaly and anemia. N Engl J Med 2008;359:2707-2718.
35. Colović N, Miljić P, Colović M, Milosević- Jovcić N, Multiple M components in two patients with splenic lymphoma with villous lymphocytes. Ann Hematol 2006;85:51-54. (Pubitemid 41786691)
36. Manner H, Jung B, Tonassi L, et al. Successful treatment of catastrophic antiphospholipid antibody syndrome (CAPS) associated with splenic marginal-zone lymphoma with lowmolecular weight heparin, rituximab and bendamustine. Am J Med Sci 2008;335:394-397.
37. McGuire D, Zeidman A, Mittelman M. Non-Hodgkin's lymphoma presenting with coagulopathy due to anti-phospholipid antibody syndrome. Leuk Lymphoma 1997;26:193-196. (Pubitemid 27351025)
38. McLean-Tooke A, Stroud C, Sampson A, Spickett G. Falsely normal C4 in a case of acquired C1 esterase inhibitor deficiency. J Clin Pathol 2007;60:565-566. (Pubitemid 46867171)
39. Murakami H, Irisawa H, Saitoh T, et al. Immunological abnormalities in splenic marginal zone cell lymphoma. Am J Hematol 1997;56:173-178. (Pubitemid 27486429)
40. Sawamura M, Yamaguchi S, Murakami H, et al. Multiple autoantibody production in a patient with splenic lymphoma. Ann Hematol 1994;68:251-254. (Pubitemid 24191897)
41. Sugisaki K, Itoh K, Tamaru J. Acquired C1-esterase inhibitor deficiency and positive lupus anticoagulant accompanied by splenic marginal zone B-cell lymphoma. Clin Exp Rheumatol 2007;25:627-629. (Pubitemid 47455474)
42. Veneri D, Ambrosetti A, Franchini M, Mosna F, Poli G, Pizzolo G. Remission of severe antiphospholipid syndrome associated with non-Hodgkin's B-cell lymphoma after combined treatment with rituximab and chemotherapy. Haematologica 2005;90(Suppl.):ECR37.
43. Voinchet H, Etienne G, Ghiringelli CB, et al. Splenic marginal zone lymphoma and autoimmunity: report of six cases. Rev Med Interne 2010;31:4-11.
44. Yokoi T, Mori S, Sugimoto H, et al. Splenic marginal zone lymphoma associated with antiphospholipid antibodies. Rinsho Ketsueki 2004;45:1095-1099.
45. Arruda VR, Bizzacchi JM, Metze IL. Hairy cell leukemia and multiple autoimmune manifestations in a human immunodeficiency virus-infected patient. Ann Hematol 1993;66: 325-327. (Pubitemid 23220776)
46. Duncombe AS, Dalton RG, Savidge GF. Lupus-type coagulation inhibitor in hairy cell leukaemia and resolution with splenectomy. Br J Haematol 1987;65:120-121.
47. Kirkpatrick J, Danks RR, Eikram M. Hairy cell leukemia with an associated lupus-type anticoagulant. J Am Osteopath Assoc 1999;99:109-12, 116.
48. Richard C, Sedano MC, Mázorra F, et al. Hairy-cell leukaemia associated with auto-immune disorders in the form of a 'lupus-type' anticoagulant and a positive direct Coombs' test. Acta Haematol 1986;75:181-182. (Pubitemid 16016176)
49. Diz-Kucukkaya R, Dincol G, Kamali S, Kural F, Inanc M. Development of hairy cell leukemia in a patient with antiphospholipid syndrome. Lupus 2007;16:286-288. (Pubitemid 46797893)
50. Shinagawa A, Kojima H, Kobayashi T, Kawada K, Nagasawa T. Lupus anticoagulant-like activity observed in a dimeric lambda protein produced by myeloma cells. Int J Hematol 2001;73:526-531. (Pubitemid 33758888)
51. Takamiya O, Machida S, Okuda M, Nojima J, Koreeda C, Kubara K. A non-immunological phospholipid-dependent coagulation inhibitor associated with IgGlambda-type multiple myeloma. Am J Hematol 2004;75:34-39. (Pubitemid 38040165)
52. Yasin Z, Quick D, Thiagarajan P, Spoor D, Caraveo J, Palascak J. Light-chain paraproteins with lupus anticoagulant activity. Am J Hematol 1999;62:99-102. (Pubitemid 29463721)
53. Gruber A, Blaskó G Sas G. Functional deficiency of protein C and skin necrosis in multiple myeloma. Thromb Res 1986;42:579-581. (Pubitemid 16073480)
54. Deitcher SR, Erban JK, Limentani SA. Acquired free protein S deficiency associated with multiple myeloma: a case report. Am J Hematol 1996;51:319-323. (Pubitemid 26116371)
55. Moore GW, Kamat AV, Gurney DA, et al. Alteration in the laboratory profile of a lupus anticoagulant in a patient with non-Hodgkin's lymphoma. Clin Lab Haematol 2004;26: 429-434. (Pubitemid 39664887)
56. Carrascosa M, Hernandez JJ, Perez-Castrillon JL, Sampedro I. Antiphospholipid antibodies and Sézary syndrome. Am J Hematol 1995;49:365.
57. Hill VA, Whittaker SJ, Hunt BJ, Liddell K, Spittle MF, Smith NP. Cutaneous necrosis associated with the antiphospholipid syndrome and mycosis fungoides. Br J Dermatol 1994;130: 92-96. (Pubitemid 24201145)
58. Onida P, Tresoldi M, Rugarli C. Anti-phospholipid-antibody syndrome associated with peripheral T-cell lymphoma. Am J Hematol 1997;55:167-168. (Pubitemid 27333345)
59. Veysey EC, Wilkinson JD. Mycosis fungoides masquerading as cutaneous lupus erythematosus and associated with antiphospholipid syndrome. Clin Exp Dermatol 2008;33:26-29. (Pubitemid 350308520)
60. Schwartz J, Gonzalez J, Rosenberg R, et al. Cutaneous T-cell lymphoma, tropical spastic paraparesis, cerebral vasculitis, and protein S deficiency in a patient with HTLV-I. South Med J 1996;89:999-1000. (Pubitemid 26347086)
61. Lai S, Walker DH, Elghetany MT. Catastrophic antiphospholipid syndrome: a rare cause of disseminated microvascular thrombotic injury - a case report with pathological and molecular correlative studies. Pathol Int 2005;55:144-149. (Pubitemid 40477225)
62. Ianotto JC, Tempescul A, Eveillard JR, Malou M, Berthou C. A possible relationship of lupus anti-coagulant with disease activity in Hodgkin lymphoma. Leuk Lymphoma 2009;50: 122-123.
63. The Non-Hodgkin's Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. Blood 1997;89:3909-3918.
64. Chacón JI, ,Mollejo M, Muñoz E, et al. Splenic marginal zone lymphoma: clinical characteristics and prognostic factors in a eries of 60 patients. Blood 2002;100:1648-1654. (Pubitemid 34925141)
65. Troussard X, Valensi F, Duchayne E, et al. Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hématologie Cellulaire (GFHC). Br J Haematol 1996;93: 731-736. (Pubitemid 26167378)
66. Kyrtsonis MC, Vassilakopoulos TP, Angelopoulou MK, et al. Waldenström's macroglobulinemia: clinical course and prognostic factors in 60 patients. Experience from a single hematology unit. Ann Hematol 2001;80:722-727.
67. Ghobrial IM, Gertz MA, Fonseca R. Waldenström macroglobulinaemia. Lancet Oncol 2003;4:679-685.
68. Treon SP, Branagan AR, Ioakimidis L, et al. Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia. Blood 2009;113:3673-3678.
69. Oberic L, Buffet M, Schwarzinger M, et al. Cancer awareness in atypical thrombotic microangiopathies. Oncologist 2009; 14:769-779.
70. Carey RW, Harris N. Thrombotic microangiopathy in three patients with cured lymphoma. Cancer 1989;63:1393-1397. (Pubitemid 19084563)
71. Sill H, Höfler G, Kaufmann P, et al. Angiotropic large cell lymphoma presenting as thrombotic microangiopathy (thrombotic thrombocytopenic purpura). Cancer 1995;75: 1167-1170.
72. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002;346:752-763. (Pubitemid 34983997)
73. Giannakopoulos B, Passam F, Ioannou Y, Krilis SA. How we diagnose the antiphospholipid syndrome. Blood 2009;113:985-994.
74. Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003;101: 1827-1832. (Pubitemid 36237580)
75. Pengo V, Ruffatti A, Legnani C, et al. Clinical course of highrisk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010;8:237-242.
76. Wahl DG, Guillemin F, de Maistre E, Perret-Guillaume C, Lecompte T, Thibaut G. Meta-analysis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 1998;7:15-22. (Pubitemid 28052657)
77. Calvo-Alén J, Toloza SM, Fernández M, et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients.Arthritis Rheum 2005;52: 2060-2068. (Pubitemid 40994330)
78. Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46:1019-1027. (Pubitemid 34303815)
79. Gómez-Puerta JA, Cervera R, Espinosa G, et al. Antiphospholipid antibodies associated with malignancies: clinical and pathological characteristics of 120 patients. Semin Arthritis Rheum 2006;35:322-332.
80. Schleider MA, Nachman RL, Jaffe EA, Coleman M. A clinical study of the lupus anticoagulant. Blood 1976;48:499-509.
81. Finazzi G. The Italian Registry of Antiphospholipid Antibodies. Haematologica 1997;82:101-105. (Pubitemid 28023500)
82. Miesbach W, Scharrer I, Asherson R. Thrombotic manifestations of the antiphospholipid syndrome in patients with malignancies. Clin Rheumatol 2006;25:840-844. (Pubitemid 44473149)
83. Berger F, Felman P, Thieblemont C, et al. Non-MALT marginal zone B-cell lymphomas: a description of clinical presentation and outcome in 124 patients. Blood 2000;95: 1950-1956. (Pubitemid 30151631)
84. Thieblemont C, Felman P, Callet-Bauchu E, et al. Splenic marginal-zone lymphoma: a distinct clinical and pathological entity. Lancet Oncol 2003;4:95-103. (Pubitemid 36193169)
85. Genvresse I, Lüftner D, Späth-Schwalbe E, Buttgereit F. Prevalence and clinical significance of anticardiolipin and antibeta2- glycoprotein-I antibodies in patients with non-Hodgkin's lymphoma. Eur J Haematol 2002;68:84-90. (Pubitemid 34478272)
86. Pusterla S, Previtali S, Marziali S, et al. Antiphospholipid antibodies in lymphoma: prevalence and clinical significance. Hematol J 2004;5:341-346. (Pubitemid 39214212)
87. Lechner K. A new type of coagulation inhibitor. Thromb Diath Haemorrh 1969;21:482-499.
88. Thiagarajan P, Shapiro SS, DeMarco L. Monoclonal immunoglobulin M lambda coagulation inhibitor with phospholipid specificity. Mechanism of a lupus anticoagulant. J Clin Invest 1980;66:397-405. (Pubitemid 10053902)
89. Hauswirth AW, Skrabs C, Schützinger C, Gaiger A, Lechner K, Jäger U. Autoimmune hemolytic anemias, Evans' syndromes, and pure red cell aplasia in non-Hodgkin lymphomas. Leuk Lymphoma 2007;48:1139-1149. (Pubitemid 47009204)
90. Mauro FR, Foa R, Cerretti R, et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood 2000;95:2786-92. (Pubitemid 30235886)
91. Kristinsson SY, Pfeiffer RM, Björkholm M, et al. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study. Blood 2010;115:4991-4998.
92. Finazzi G, Brancaccio V, Moia M, et al. Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four-year prospective study from the Italian Registry. Am J Med 1996;100:530-536. (Pubitemid 26170477)
93. Kasturi J, Saraya AK. Platelet functions in dysproteinaemia. Acta Haematol 1978;59:104-113. (Pubitemid 8253213)
94. Lockshin MD, Erkan D. Treatment of the antiphospholipid syndrome. N Engl J Med 2003;349:1177-1179. (Pubitemid 37122331)
95. Ahn ER, Lander G, Bidot CJ, Jy W, Ahn YS. Long-term remission from life-threatening hypercoagulable state associated with lupus anticoagulant (LA) following rituximab therapy. Am J Hematol 2005;78:127-129. (Pubitemid 40194105)
96. Tomietto P, Gremese E, Tolusso B, Venturini P, De Vita S, Ferraccioli G. B cell depletion may lead to normalization of anti-platelet, anti-erythrocyte and antiphospholipid antibodies in systemic lupus erythematosus. Thromb Haemost 2004;92: 1150-1153. (Pubitemid 39545542)
97. Stahl CP, Wideman CS, Spira TJ, Haff EC, Hixon GJ, Evatt BL. Protein S deficiency in men with long-term human immunodeficiency virus infection. Blood 1993;81:1801-1807. (Pubitemid 23101593)