Skip to main content Accessibility help
×
Hostname: page-component-7c8c6479df-5xszh Total loading time: 0 Render date: 2024-03-28T12:17:26.951Z Has data issue: false hasContentIssue false

Chapter 10 - Pediatric thrombophilia evaluation: Considerations for primary and secondary venous thromboembolism prevention

from Section 2 - Special considerations in pediatric patients

Published online by Cambridge University Press:  18 December 2014

Ulrike Nowak-Göttl
Affiliation:
University Hospital of Kiel & Lübeck
Gili Kenet
Affiliation:
Sheba Medical Center
Neil A. Goldenberg
Affiliation:
Johns Hopkins University School of Medicine
Neil A. Goldenberg
Affiliation:
The Johns Hopkins University School of Medicine
Marilyn J. Manco-Johnson
Affiliation:
Hemophilia and Thrombosis Center, University of Colorado, Denver
Get access

Summary

Introduction

Venous thromboembolism (venous TE; VTE) is a rare disease that was increasingly recognized and diagnosed in pediatrics in the past decade, usually as a secondary complication of primary underlying diseases such as sepsis, cancer, congenital heart disease, elevated endogenous testosterone, or after therapeutic interventions such as central venous lines (Table 10.1) [1–13]. Pediatric VTE is a severe disease for which long-term outcomes include lack of thrombus resolution in 50% of cases and the development of post-thrombotic syndrome (PTS) in nearly one-fourth of patients [8–11]. Within the entire childhood population, neonates are at the greatest risk for VTE (5.1/100,000 live births per year in Caucasian children) [1,2,6,14], with a second peak in incidence during puberty and adolescence. The annual incidence of venous events was estimated to be 0.07 to 0.14 per 10,000 children, or 5.3 per 10,000 hospital admissions of children and 24 per 10,000 admissions of neonates to neonatal intensive care units [1,6,12–14].

To date, the results of single studies on the risk of VTE onset and recurrence associated with inherited thrombophilia (IT) are contradictory or inconclusive, mainly due to lack of statistical power. Apart from acquired thrombophilic abnormalities such as antiphospholipid antibodies [15–17], deficiencies of antithrombin, protein C, or protein S and the coagulation factor V (G1691A), and factor II (G20210A) variants have been established as risk factors for incident VTE events in adults [18–23]. The ITs have been described as additional risk factors in populations of children with provoked and unprovoked VTE, with and without underlying disease [24–56].

Follow-up data for VTE recurrence in children are available from a few reports and suggest a recurrence rate of approximately 3% in neonates, 6–11% at 2 years in largely unselected cases (provoked and unprovoked incident VTE), and 21% in children with unprovoked VTE [7,10,12,13,38,48,49,51,54,56].

Type
Chapter
Information
Publisher: Cambridge University Press
Print publication year: 2015

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Andrew, M, David, M, Adams, M, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood. 1994;83:1251–1257.Google ScholarPubMed
Schmidt, B, Andrew, M. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics. 1995;96:939–943.Google ScholarPubMed
Journeycake, JM, Buchanan, GR. Thrombotic complications of central venous catheters in children. Cur Opin Hematol. 2003;10:369–374.CrossRefGoogle ScholarPubMed
Revel-Vilk, S. Central venous line-related thrombosis in children. Acta Haematol. 2006;115:201–206.CrossRefGoogle ScholarPubMed
Normann, S, deVeber, G, Fobker, M, et al. Role of endogenous testosterone concentration in pediatric stroke. Ann Neurol. 2009;66:754–758.CrossRefGoogle ScholarPubMed
Nowak-Göttl, U, von Kries, R, Göbel, U. Neonatal symptomatic thromboembolism in Germany: two year survey. Arch Dis Child Fetal Neonatal Ed. 1997;76:F163–167.CrossRefGoogle ScholarPubMed
Revel-Vilk, S, Sharathkumar, A, Massicotte, P, et al. Natural history of arterial and venous thrombosis in children treated with low molecular weight heparin: a longitudinal study by ultrasound. J Thromb Haemost. 2004;2:42–46.CrossRefGoogle ScholarPubMed
Goldenberg, NA, Donadini, MP, Kahn, SR, et al. Post-thrombotic syndrome in children: a systematic review of frequency of occurrence, validity of outcome measures, and prognostic factors. Haematologica. 2010;95:1952–1959.CrossRefGoogle ScholarPubMed
Journeycake, J, Eshelman, D, Buchanan, GR. Post-thrombotic syndrome is uncommon in childhood cancer survivors. J Pediatr. 2006;148:275–277.CrossRefGoogle ScholarPubMed
Goldenberg, NA. Long-term outcomes of venous thrombosis in children. Curr Opin Hematol. 2005;12: 370–376.CrossRefGoogle ScholarPubMed
Kuhle, S, Koloshuk, B, Marzinotto, V, et al. A cross-sectional study evaluating post-thrombotic syndrome in children. Thromb Res. 2003;111:227–233.CrossRefGoogle ScholarPubMed
Massicotte, MP, Dix, D, Monagle, P, et al. Central venous catheter-related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications. J Pediatr. 1998;133:770–776.CrossRefGoogle ScholarPubMed
Monagle, P, Adams, M, Mahoney, M, et al. Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr Res. 2000;47:763–766.CrossRefGoogle ScholarPubMed
van Ommen, CH, Heijboer, H, Büller, HR, et al. Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Pediatr. 2001;139:676–681.CrossRefGoogle ScholarPubMed
Levy, DM, Massicotte, MP, Harvey, E, et al. Thromboembolism in paediatric lupus patients. Lupus. 2003;12:741–746.CrossRefGoogle ScholarPubMed
Berkun, Y, Padeh, S, Barash, J, et al. Antiphospholipid syndrome and recurrent thrombosis in children. Arthritis Rheum. 2006;55:850–855.CrossRefGoogle ScholarPubMed
Günes, AM, Baytan, B, Günay, U. The influence of risk factors in promoting thrombosis during childhood: the role of acquired factors. Pediatr Hematol Oncol. 2006;23:399–410.CrossRefGoogle ScholarPubMed
Salomon, O, Steinberg, DM, Zivelin, A, et al. Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment. Arterioscler Thromb Vasc Biol. 1999;19:511–518.CrossRefGoogle ScholarPubMed
Ehrenforth, S, von Depka Prondsinski, M, Aygören-Pürsün, E, et al. Study of the prothrombin gene 20201 GA variant in FV: Q 506 carriers in relationship to the presence or absence of juvenile venous thromboembolism. Arterioscler Thromb Vac Biol. 1999;19:276–280.CrossRefGoogle ScholarPubMed
Prandoni, P, Lensing, AW, Cogo, A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125:1–7.CrossRefGoogle ScholarPubMed
van den Belt, AG, Sanson, BJ, Simioni, P, et al. Recurrence of venous thromboembolism in patients with familial thrombophilia. Arch Intern Med. 1997;157:2227–2232.CrossRefGoogle ScholarPubMed
Simioni, P, Sanson, BJ, Prandoni, P, et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost. 1999 81:198–202.CrossRefGoogle ScholarPubMed
Sofi, F, Marcucci, R, Abbate, R, et al. Lipoprotein(a) and venous thromboembolism in adults: a meta-analysis. Am J Med. 2007;120:728–733.CrossRefGoogle ScholarPubMed
Nuss, R, Hays, T, Manco-Johnson, M. Childhood thrombosis. Pediatrics. 1995;96:291–294.Google ScholarPubMed
Nowak-Göttl, U, Koch, HG, Aschka, I, et al. Resistance to activated protein C (APCR) in children with venous or arterial thromboembolism. Br J Haematol. 1996;92:992–998.CrossRefGoogle ScholarPubMed
Aschka, I, Aumann, V, Bergmann, F, et al. Prevalence of factor V Leiden in children with thromboembolism. Eur J Pediatr. 1996;155:1009–1014.CrossRefGoogle Scholar
Uttenreuther-Fischer, MM, Vetter, B, Hellmann, C, et al. Paediatric thrombo-embolism: the influence of non-genetic factors and the role of activated protein C resistance and protein C deficiency. Eur J Pediatr. 1997;156:277–281.CrossRefGoogle ScholarPubMed
Sifontes, MT, Nuss, R, Hunger, SP, et al. The factor V Leiden mutation in children with cancer and thrombosis. Br J Haematol. 1997;96:484–489.CrossRefGoogle ScholarPubMed
Toumi, NH, Khaldi, F, Ben Becheur, S, et al. Thrombosis in congenital deficiencies of AT III, protein C or protein S: a study of 44 children. Hematol Cell Ther. 1997;39:295–299.CrossRefGoogle ScholarPubMed
Sifontes, MT, Nuss, R, Hunger, SP, et al. Activated protein C resistance and the factor V Leiden mutation in children with thrombosis. Am J Hematol. 1998;57:29–32.3.0.CO;2-3>CrossRefGoogle ScholarPubMed
Hagstrom, JN, Walter, J, Bluebond-Langner, R, et al. Prevalence of the factor V Leiden mutation in children and neonates with thromboembolic disease. J Pediatr. 1998;133:777–781.CrossRefGoogle ScholarPubMed
Ehrenforth, S, Junker, R, Koch, HG, et al. Multicentre evaluation of combined prothrombotic defects associated with thrombophilia in childhood. Childhood Thrombophilia Study Group. Eur J Pediatr. 1999;158:S97–104.CrossRefGoogle ScholarPubMed
Schobess, R, Junker, R, Auberger, K, et al. Factor V G1691A and prothrombin G20210A in childhood spontaneous venous thrombosis – evidence of an age-dependent thrombotic onset in carriers of the factor V G1691A and prothrombin G20210A mutation. Eur J Pediatr. 1999;158:S105–108.CrossRefGoogle ScholarPubMed
Nowak-Göttl, U, Junker, R, Hartmeier, M, et al. Increased lipoprotein (a) is an important risk factor for venous thromboembolism in childhood. Circulation. 1999;100:743–748.CrossRefGoogle ScholarPubMed
Lawson, SE, Butler, D, Enayat, MS, Williams, MD. Congenital thrombophilia and thrombosis: a study in a single centre. Arch Dis Child. 1999;81:176–178.CrossRefGoogle Scholar
Junker, R, Koch, HG, Auberger, K, et al. Prothrombin G20210A gene mutation and further prothrombotic risk factors in childhood thrombophilia. Arterioscler Thromb Vasc Biol. 1999;19:2568–2572.CrossRefGoogle ScholarPubMed
Kuhle, S, Lane, DA, Jochmanns, K, et al. Homozygous antithrombin deficiency type II (99 Leu to Phe mutation) and childhood thromboembolism. Thromb Haemost. 2001;86:1007–1011.CrossRefGoogle ScholarPubMed
Nowak-Göttl, U, Junker, R, Kreuz, W, et al. Childhood Thrombophilia Study Group. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Blood. 2001;97:858–862.CrossRefGoogle Scholar
deVeber, G, Andrew, M, Adams, C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345:417–423.CrossRefGoogle ScholarPubMed
Revel-Vilk, S, Chan, A, Bauman, M, Massicotte, P. Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease. J Thromb Haemost. 2003;1:915–921.CrossRefGoogle Scholar
Bonduel, M, Hepner, M, Sciuccati, G, et al. Factor V Leiden and prothrombin gene G20210A mutation in children with venous thromboembolism. Thromb Haemost. 2002;87:972–977.Google ScholarPubMed
van Ommen, CH, Heijboer, H, van den Dool, EJ, et al. Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome. J Thromb Haemost. 2003;1:2516–2522.CrossRefGoogle ScholarPubMed
Young, G, Manco-Johnson, M, Gill, JC, et al. Clinical manifestations of the prothrombin G20210A mutation in children: a pediatric coagulation consortium study. J Thromb Haemost. 2003;1:958–962.CrossRefGoogle ScholarPubMed
Atasay, B, Arsan, S, Günlemez, A, et al. Factor V Leiden and prothrombin gene 20210A variant in neonatal thromboembolism and in healthy neonates and adults: a study in a single center. Pediatr Hematol Oncol. 2003;20:627–634.CrossRefGoogle Scholar
Heller, C, Heinecke, A, Junker, R, et al. Cerebral venous thrombosis in children: a multifactorial origin. Circulation. 2003;108:1362–1367.CrossRefGoogle ScholarPubMed
El-Karaksy, H, El-Koofy, N, El-Hawary, M, et al. Prevalence of factor V Leiden mutation and other hereditary thrombophilic factors in Egyptian children with portal vein thrombosis: results of a single-center case-control study. Ann Hematol. 2004;83:712–715.CrossRefGoogle ScholarPubMed
Kenet, G, Waldman, D, Lubetsky, A, et al. Paediatric cerebral sinus vein thrombosis. A multi-center, case-controlled study. Thromb Haemost. 2004;92:713–718.Google ScholarPubMed
Goldenberg, NA, Knapp-Clevenger, R, Manco- Johnson, MJ, Mountain States Regional Thrombophilia Group. Elevated plasma factor VIII and D-dimer levels as predictors of poor outcomes of thrombosis in children. New Engl J Med. 2004;351:1081–1088.CrossRefGoogle ScholarPubMed
Kosch, A, Kuwertz-Bröking, E, Heller, C, et al. Renal venous thrombosis in neonates: prothrombotic risk factors and long-term follow-up. Blood. 2004;104:1356–1360.CrossRefGoogle ScholarPubMed
Rask, O, Berntorp, E, Ljung, R. Risk factors for venous thrombosis in Swedish children and adolescents. Acta Paediatr. 2005;94:717–722.CrossRefGoogle ScholarPubMed
Marks, SD, Massicotte, P, Steele, BT, et al. Neonatal renal venous thrombosis: clinical outcomes and prevalence of prothrombotic disorders. J Pediatr. 2005;146:811–816.CrossRefGoogle ScholarPubMed
Brandão, LR, Williams, S, Kahr, WH, et al. Exercise-induced deep vein thrombosis of the upper extremity. 2. A case series in children. Acta Haematol. 2006;115:214–220.CrossRefGoogle ScholarPubMed
Tavil, B, Ozyurek, E, Gumruk, F, et al. Antiphospholipid antibodies in Turkish children with thrombosis. Blood Coagul Fibrinol. 2007;18:347–352.CrossRefGoogle ScholarPubMed
Kreuz, W, Stoll, M, Junker, R, et al. Familial elevated factor VIII in children with symptomatic venous thrombosis and post-thrombotic syndrome: results of a multicenter study. Arterioscler Thromb Vasc Biol. 2006;26:1901–1906.CrossRefGoogle ScholarPubMed
Albisetti, M, Moeller, A, Waldvogel, K, et al. Congenital prothrombotic disorders in children with peripheral venous and arterial thromboses. Acta Haematol. 2007;117:149–155.CrossRefGoogle ScholarPubMed
Kenet, G, Kirkham, F, Niederstadt, T, et al. Risk factors for recurrent venous thromboembolism in the European collaborative paediatric database on cerebral venous thrombosis: a multicentre cohort study. Lancet Neurol. 2007;6:595–603.CrossRefGoogle ScholarPubMed
Andrew, M, Paes, B, Milner, R, et al. Development of the human coagulation system in the full-term infant. Blood. 1987;70:165–172.Google ScholarPubMed
Andrew, M, Vegh, P, Johnston, M, Bowker, J, Ofosu, F, Mitchell, L. Maturation of the hemostatic system during childhood. Blood. 1992;80:1998–2005.Google ScholarPubMed
Ignjatovic, V, Lai, C, Summerhayes, R, et al. Age-related differences in plasma proteins: how plasma proteins change from neonates to adults. PLoS One 2011;6(2):e17213.CrossRefGoogle ScholarPubMed
Mari, D, Mannucci, PM, Coppola, R, et al. Hypercoagulability in centenarians: the paradox of successful aging. Blood. 1995;85:3144–3149.Google ScholarPubMed
Bjarke, B, Herin, P, Blomback, M. Neonatal aortic thrombosis. A possible clinical manifestation of congenital antithrombin 3 deficiency. Acta Paediatr Scand. 1974;63:297–301.CrossRefGoogle ScholarPubMed
De Stefano, V, Leone, G, Ferrelli, R, et al. Severe deep vein thrombosis in a 2-year-old child with protein S deficiency. Thromb Haemost. 1987;58:1089.Google Scholar
Israels, SJ, Seshia, SS. Childhood stroke associated with protein C or S deficiency. J Pediatr. 1987;111:562–564.CrossRefGoogle ScholarPubMed
Mannino, FL, Trauner, DA. Stroke in neonates. J Pediatr. 1983;102(4):605–610.CrossRefGoogle ScholarPubMed
Shapiro, ME, Rodvien, R, Bauer, KA, Salzman, EW. Acute aortic thrombosis in antithrombin III deficiency. JAMA. 1981;245:1759–1761.CrossRefGoogle ScholarPubMed
Andrassy, K, Ritz, E, Bommer, J. Hypercoagulability in the nephrotic syndrome. Klin Wochenschr. 1980;58:1029–1036.CrossRefGoogle ScholarPubMed
Kanfer, A, Kleinknecht, D, Broyer, M, Josso, F. Coagulation studies in 45 cases of nephrotic syndrome without uremia. Thromb Diath Haemorrh. 1970;24:562–571.Google ScholarPubMed
Kauffmann, RH, Veltkamp, JJ, Van Tilburg, NH, Van Es, LA. Acquired antithrombin III deficiency and thrombosis in the nephrotic syndrome. Am J Med 1978;65:607–613.CrossRefGoogle ScholarPubMed
Kuhlmann, U, Blattler, W, Pouliadis, G, Siegenthaler, W. Complications of nephrotic syndrome with special reference to thromboembolic accidents. Schweiz Med Wochenschr. 1979;109:200–209.Google ScholarPubMed
Schrader, J, Kostering, H, Zuchner, C, al. Antithrombin III-Bestimmung im Schnelltest: Ein Vergleich mit Partigen-Platten undeinem chromogenen Substrat. Lab Med. 1981;5:211–218.Google Scholar
Thaler, E, Balzar, E, Kopsa, H, Pinggera, WF. Acquired antithrombin III deficiency in patients with glomerular proteinuria. Haemostasis. 1978;7:257–272.Google ScholarPubMed
Hanson, SJ, Punzalan, RC, Greenup, RA et al. Incidence and risk factors for venous thromboembolism in critically ill children after trauma. J Trauma. 2010;68:52–56.CrossRefGoogle ScholarPubMed
Young, G, Albisetti, M, Bonduel, M, et al. Impact of inherited thrombophilia on venous thromboembolism in children: A systematic review & meta-analysis of observational studies. Circulation. 2008;118:1373–1382.CrossRefGoogle ScholarPubMed
Kenet, G, Lütkhoff, LK, Albisetti, M, et al. Impact of inherited thrombophilia on arterial ischemic stroke and cerebral sinovenous thrombosis in children: a systematic review and meta-analysis of observational studies. Circulation. 2010;121:1838–1847.CrossRefGoogle Scholar
Kenet, G, Aronis, S, Berkun, Y, et al. Impact of persistent antiphospholipid antibodies on symptomatic thromboembolism in children: A systematic review & meta-analysis [observational studies]. Semin Thromb Haemost. 2011;37:802–809.CrossRefGoogle Scholar
Avčin, T, Cimaz, R, Silverman, ED, et al. Pediatric antiphospholipid syndrome: clinical and immunologic features of 121 patients in an international registry. Pediatrics. 2008;122:e1100–1107.CrossRefGoogle Scholar
Goldenberg, NA, Donadini, MP, Kahn, SR, Crowther, M, Kenet, G, Nowak-Göttl, U, Manco-Johnson, MJ. Post-thrombotic syndrome in children: a systematic review of frequency of occurrence, validity of outcome measures, and prognostic factors. Haematologica. 2010;95:1952–1959.CrossRefGoogle ScholarPubMed
Goldenberg, NA, Durham, JD, Knapp-Clevenger, R, Manco-Johnson, MJ. A thrombolytic regimen for high-risk deep venous thrombosis may substantially reduce the risk of postthrombotic syndrome in children. Blood. 2007;110:45–53.CrossRefGoogle ScholarPubMed
Lyle, CA, Gibson, E, Lovejoy, AE, Goldenberg, NA. Acute prognostic factors for post-thrombotic syndrome in children with limb DVT: a bi-institutional cohort study. Thromb Res. 2013;131:37–41.CrossRefGoogle ScholarPubMed
Holzhauer, S, Goldenberg, NA, Junker, R, et al. Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: An observational study. Blood. 2012;120:1510–1515.CrossRefGoogle Scholar
Calhoon, MJ, Ross, CN, Pounder, E, Cassidy, D, Manco-Johnson, MJ, Goldenberg, NA. High prevalence of thrombophilic traits in children with family history of thromboembolism. J Pediatr. 2010;157:485–489.CrossRefGoogle ScholarPubMed
Nowak-Göttl, U, Langer, C, Bergs, S, et al. Genetics of hemostasis: differential effects of heritability and household components influencing lipid concentrations and clotting factor levels in 282 pediatric stroke families. Environ Health Perspect. 2008;116:839–843.CrossRefGoogle ScholarPubMed
Arning, A, Hiersche, M, Bidlingmaier, C, et al. A Genome-Wide Association Study Identifies Novel Susceptibility Genes for Pediatric Venous Thrombosis. Blood (ASH Annual Meeting Abstracts). Nov 2011;118:3336.Google Scholar
Vossen, CY, Walker, ID, Svensson, P, et al. Recurrence rate after first venous thrombosis in patients with familial thrombophilia. Arterioscler Thromb Vasc Biol. 2005;25:1992–1997.CrossRefGoogle ScholarPubMed
De Stefano, V, Rossi, E, Paciaroni, K, Leone, G. Screening for inherited thrombophilia: indications and therapeutic implications. Haematologica. 2002;87:1095–1108.Google ScholarPubMed
Prandoni, P, Noventa, F, Ghirarduzzi, A, et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica. 2007;92:199–205.CrossRefGoogle ScholarPubMed
Lindmarker, P, Schulman, S, Sten-Linder, M, Wiman, B, Egberg, N, Johnsson, H. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation. Thromb Haemost. 1999;81:684–9.Google Scholar
Büller, H, Agnelli, G, Hull, RD, et al. Antithrombotic therapy for venous thromboembolic disease. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126:S401–428.CrossRefGoogle ScholarPubMed
Monagle, P, Chan, AK, Goldenberg, NA et al; American College of Chest Physicians. Antithrombotic Therapy in Neonates and Children: Antithrombotic Therapy and Prevention of Thrombosis, 9th edn: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e737S–801S.CrossRefGoogle Scholar
Bidlingmaier, C, Kenet, G, Kurnik, K, et al. Safety and efficacy of low molecular weight heparin in children: a systematic review of the literature and meta-analysis of single-arm studies. Semin Thromb Hemost. 2011;37:814–25.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×