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Aspirin in pregnant patients with essential thrombocythemia: a retrospective analysis of 129 pregnancies

2009; Elsevier BV; Volume: 8; Issue: 2 Linguagem: Inglês

10.1111/j.1538-7836.2009.03686.x

1538-7933

Francesco Passamonti, Elisa Rumi, Maria Luigia Randi, Enrica Morra, Mario Cazzola,

Acute Myeloid Leukemia Research

Essential thombocythemia (ET) is the most frequent myeloproliferative neoplasm [1Tefferi A. Thiele J. Orazi A. Kvasnicka H.M. Barbui T. Hanson C.A. Barosi G. Verstovsek S. Birgegard G. Mesa R. Reilly J.T. Gisslinger H. Vannucchi A.M. Cervantes F. Finazzi G. Hoffman R. Gilliland D.G. Bloomfield C.D. Vardiman J.W. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel.Blood. 2007; 110: 1092-7Crossref PubMed Scopus (763) Google Scholar] with a high risk of thrombotic complications [2Passamonti F. Rumi E. Pascutto C. Cazzola M. Lazzarino M. Increase in leukocyte count over time predicts thrombosis in patients with low‐risk essential thrombocythemia.J Thromb Haemost. 2009; 7: 1587-910.1111/j.1538‐7836.2009.03531.xCrossref PubMed Scopus (29) Google Scholar]. Information concerning molecular abnormalities of ET has been scanty until 2005, when a Janus kinase 2 mutation, namely JAK2 (V617F), was discovered in 50–60% of these patients [3Kralovics R. Passamonti F. Buser A.S. Teo S.S. Tiedt R. Passweg J.R. Tichelli A. Cazzola M. Skoda R.C. A gain‐of‐function mutation of JAK2 in myeloproliferative disorders.N Engl J Med. 2005; 352: 1779-90Crossref PubMed Scopus (2948) Google Scholar]. This mutation gives ET patients a typical clinical phenotype [4Campbell P.J. Scott L.M. Buck G. Wheatley K. East C.L. Marsden J.T. Duffy A. Boyd E.M. Bench A.J. Scott M.A. Vassiliou G.S. Milligan D.W. Smith S.R. Erber W.N. Bareford D. Wilkins B.S. Reilly J.T. Harrison C.N. Green A.R. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study.Lancet. 2005; 366: 1945-53Abstract Full Text Full Text PDF PubMed Scopus (601) Google Scholar]. Essential thrombocythemia is more frequent in women and the rate of young patients ranges from 15% to 20%. Pregnancy in ET patients has a higher risk of complications than in the general population [5Passamonti F. Randi M.L. Rumi E. Pungolino E. Elena C. Pietra D. Scapin M. Arcaini L. Tezza F. Moratti R. Pascutto C. Fabris F. Morra E. Cazzola M. Lazzarino M. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation.Blood. 2007; 110: 485-9Crossref PubMed Scopus (127) Google Scholar, 6Melillo L. Tieghi A. Candoni A. Radaelli F. Ciancia R. Specchia G. Martino B. Scalzulli P.R. Latagliata R. Palmieri F. Usala E. Valente D. Valvano M.R. Cedrone M. Comitini G. Martinelli V. Cascavilla N. Gugliotta L. Outcome of 122 pregnancies in essential thrombocythemia patients: a report from the Italian registry.Am J Hematol. 2009; 84: 636-40Crossref PubMed Scopus (59) Google Scholar]. The JAK2 (V617F) mutation was identified as an independent predictor of pregnancy complications in two large studies [5Passamonti F. Randi M.L. Rumi E. Pungolino E. Elena C. Pietra D. Scapin M. Arcaini L. Tezza F. Moratti R. Pascutto C. Fabris F. Morra E. Cazzola M. Lazzarino M. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation.Blood. 2007; 110: 485-9Crossref PubMed Scopus (127) Google Scholar, 6Melillo L. Tieghi A. Candoni A. Radaelli F. Ciancia R. Specchia G. Martino B. Scalzulli P.R. Latagliata R. Palmieri F. Usala E. Valente D. Valvano M.R. Cedrone M. Comitini G. Martinelli V. Cascavilla N. Gugliotta L. Outcome of 122 pregnancies in essential thrombocythemia patients: a report from the Italian registry.Am J Hematol. 2009; 84: 636-40Crossref PubMed Scopus (59) Google Scholar]. In contrast, this mutation seemed not to affect spontaneous miscarriage rates in the Mayo Clinic study [7Gangat N. Wolanskyj A.P. Schwager S. Tefferi A. Predictors of pregnancy outcome in essential thrombocythemia: a single institution study of 63 pregnancies.Eur J Haematol. 2009; 82: 350-3Crossref PubMed Scopus (73) Google Scholar]. Treatment of ET patients during pregnancy is controversial, with the need to balance the beneficial effect on pregnancy outcome against the risk of iatrogenic fetal injury [8Tefferi A. Passamonti F. Essential thrombocythemia and pregnancy: observations from recent studies and management recommendations.Am J Hematol. 2009; 84: 629-30Crossref PubMed Scopus (32) Google Scholar, 9Harrison C. Pregnancy and its management in the Philadelphia negative myeloproliferative diseases.Br J Haematol. 2005; 129: 293-306Crossref PubMed Scopus (105) Google Scholar]. Low dose aspirin has been frequently used during pregnancy and it is considered safe for the fetus without a significant risk of bleeding for the mother [10CLASP (Collaborative Low‐dose Aspirin Study in Pregnancy) Collaborative GroupCLASP: a randomised trial of low‐dose aspirin for the prevention and treatment of pre‐eclampsia among 9364 pregnant women.Lancet. 1994; 343: 619-29Abstract PubMed Scopus (933) Google Scholar]. The role of aspirin in the prevention of pregnancy complications in ET is controversial [5Passamonti F. Randi M.L. Rumi E. Pungolino E. Elena C. Pietra D. Scapin M. Arcaini L. Tezza F. Moratti R. Pascutto C. Fabris F. Morra E. Cazzola M. Lazzarino M. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation.Blood. 2007; 110: 485-9Crossref PubMed Scopus (127) Google Scholar, 6Melillo L. Tieghi A. Candoni A. Radaelli F. Ciancia R. Specchia G. Martino B. Scalzulli P.R. Latagliata R. Palmieri F. Usala E. Valente D. Valvano M.R. Cedrone M. Comitini G. Martinelli V. Cascavilla N. Gugliotta L. Outcome of 122 pregnancies in essential thrombocythemia patients: a report from the Italian registry.Am J Hematol. 2009; 84: 636-40Crossref PubMed Scopus (59) Google Scholar, 7Gangat N. Wolanskyj A.P. Schwager S. Tefferi A. Predictors of pregnancy outcome in essential thrombocythemia: a single institution study of 63 pregnancies.Eur J Haematol. 2009; 82: 350-3Crossref PubMed Scopus (73) Google Scholar, 11Niittyvuopio R. Juvonen E. Kaaja R. Oksanen K. Hallman H. Timonen T. Ruutu T. Pregnancy in essential thrombocythaemia: experience with 40 pregnancies.Eur J Haematol. 2004; 73: 431-6Crossref PubMed Scopus (51) Google Scholar]. To assess the role of aspirin in the prevention of pregnancy complications in patients with ET, we investigated 129 pregnancies in 78 patients between 1980 and 2009. Some of these patients had been included in a prior study.[5Passamonti F. Randi M.L. Rumi E. Pungolino E. Elena C. Pietra D. Scapin M. Arcaini L. Tezza F. Moratti R. Pascutto C. Fabris F. Morra E. Cazzola M. Lazzarino M. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation.Blood. 2007; 110: 485-9Crossref PubMed Scopus (127) Google Scholar] Within these pregnancies, 113 had the JAK2 (V617F) status: 64 (57%) pregnancies occurred in JAK2 (V617F)‐positive patients and 49 (43%) in JAK2 wild‐type patients. Aspirin at a daily dose of 100 mg was administered during the course of 73 (65%) pregnancies. Interferon was continued in three patients. As a first step, we evaluated pregnancy complications in the first pregnancy (n= 78). We found that aspirin was not effective in preventing pregnancy complications (n= 31), either in JAK2 (V617F)‐positive or in JAK2 wild‐type patients. Given that the outcome of a pregnancy has been demonstrated not to be influenced by the outcome of a previous pregnancy [5Passamonti F. Randi M.L. Rumi E. Pungolino E. Elena C. Pietra D. Scapin M. Arcaini L. Tezza F. Moratti R. Pascutto C. Fabris F. Morra E. Cazzola M. Lazzarino M. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation.Blood. 2007; 110: 485-9Crossref PubMed Scopus (127) Google Scholar], we evaluated the 113 pregnancies as a whole. Overall, 50 (44%) of 113 pregnancies were complicated. Fetal loss accounted for 34 (30%) events and intrauterine growth retardation for seven (6%), while maternal complications included pre‐eclampsia in five cases (4%) and arterial hypertension in four (4%) cases. Within the JAK2 (V617F)‐positive pregnancies, complications occurred in 15 (36%) out of 42 patients receiving aspirin and in 15 (68%) out of 22 who did not receive aspirin (Fig. 1). Two‐tailed Fisher exact test showed that complications were significantly lower in patients who received aspirin (P= 0.018). Within the JAK2 (V617F)‐negative pregnancies, complications occurred in 15 (48%) out of 31 patients receiving aspirin and in 5 (28%) out of 18 not receiving aspirin (P= 0.22). When restricting the analysis to first‐trimester miscarriage, aspirin was not effective in both categories (JAK2 mutated and wild‐type). The retrospective design of the present study does not permit definitive conclusions regarding the use of aspirin to prevent pregnancy complications in ET. However, these results suggest the effectiveness of aspirin in the prevention of pregnancy complications in JAK2 (V617F)‐positive patients with ET without any significant efficacy in JAK2 wild‐type patients. The interplay between the JAK2 (V617F) mutation, leukocyte/platelet activation and pregnancy complications may be a potential explanation for our finding. A relationship between the JAK2 (V617F) mutation and leukocyte/platelet activation has been documented in ET [12Falanga A. Marchetti M. Vignoli A. Balducci D. Russo L. Guerini V. Barbui T. V617F JAK‐2 mutation in patients with essential thrombocythemia: relation to platelet, granulocyte, and plasma hemostatic and inflammatory molecules.Exp Hematol. 2007; 35: 702-11Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 13Arellano‐Rodrigo E. Alvarez‐Larran A. Reverter J.C. Villamor N. Colomer D. Cervantes F. Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status.Haematologica. 2006; 91: 169-75PubMed Google Scholar, 14Passamonti F. Rumi E. Pietra D. Della Porta M.G. Boveri E. Pascutto C. Vanelli L. Arcaini L. Burcheri S. Malcovati L. Lazzarino M. Cazzola M. Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders.Blood. 2006; 107: 3676-82Crossref PubMed Scopus (210) Google Scholar]. Leukocyte/platelet activation is, at least in part, implicated in the pathophysiology of pregnancy complications in healthy subjects [15Erez O. Gotsch F. Mazaki‐Tovi S. Vaisbuch E. Kusanovic J.P. Kim C.J. Chaiworapongsa T. Hoppensteadt D. Fareed J. Than N.G. Nhan‐Chang C.L. Yeo L. Pacora P. Mazor M. Hassan S.S. Mittal P. Romero R. Evidence of maternal platelet activation, excessive thrombin generation, and high amniotic fluid tissue factor immunoreactivity and functional activity in patients with fetal death.J Matern Fetal Neonatal Med. 2009; 22: 672-8710.1080/14767050902853117Crossref PubMed Scopus (47) Google Scholar, 16Lok C.A. Jebbink J. Nieuwland R. Faas M.M. Boer K. Sturk A. Van Der Post J.A. Leukocyte activation and circulating leukocyte‐derived microparticles in preeclampsia.Am J Reprod Immunol. 2009; 61: 346-5910.1111/j.1600‐0897.2009.00701.xCrossref PubMed Scopus (61) Google Scholar]. The ability of aspirin to prevent in vitro leukocyte/platelet activation in ET [17Falanga A. Marchetti M. Vignoli A. Balducci D. Barbui T. Leukocyte‐platelet interaction in patients with essential thrombocythemia and polycythemia vera.Exp Hematol. 2005; 33: 523-30Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar] as well as in pregnancy in healthy subjects [18Vaughan J.E. Walsh S.W. Ford G.D. Thromboxane mediates neutrophil superoxide production in pregnancy.Am J Obstet Gynecol. 2006; 195: 1415-2010.1016/j.ajog.2006.02.053Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar] is well known. So, platelets and leukocytes may have a critical role in pregnancy complications of ET patients, being potentially activated by the JAK2 mutation and inhibited by aspirin. In conclusion, the findings in the current study suggest that aspirin may be effective during the pregnancy of ET patients, especially when the JAK2 (V617F) mutation is present. However, the use of aspirin in pregnancy deserves further investigation in a prospective trial. Grants were received from Fondazione Cariplo, Associazione Italiana per la Ricerca sul Cancro (AIRC), Alleanza Contro il Cancro for the Pavia group, and the Ministero Italiano della Università e Ricerca for the Padova group. The authors state that they have no conflict of interest.