1352 Letters to the Editor
heparin prophylaxis, we should adopt the policy of ‘Primum non nocere (First, do no harm)’ and we should wait and watch patients closely in the management of cancerassociated sDIC, especially those with chemosensitive tumors who are receiving antineoplastic therapy. I would like the authors to reconsider their recommendation regarding heparin prophylaxis in sDIC.
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Disclosure of Conflict of Interests The author states that he has no conflict of interest. References 1 Thachil J, Falanga A, Levi M, Liebman H, Di Nisio M. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH. J Thromb Haemost 2015; 13: 671–5. 2 http://www.gpnotebook.co.uk/simplepage.cfm?ID=-1154154493. Accessed 25 February 2015 3 Perry JR, Julian JA, Laperriere NJ, Geerts W, Agnelli G, Rogers LR, Malkin MG, Sawaya R, Baker R, Falanga A, Parpia S,
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Finch T, Levine MN. PRODIGE: a randomized placebocontrolled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost 2010; 8: 1959–65. Agnelli G, George DJ, Kakkar AK, Fisher W, Lassen MR, Mismetti P, Mouret P, Chaudhari U, Lawson F, Turpie AG; SAVE-ONCO Investigators. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 2012; 366: 601–9. Agnelli G, Gussoni G, Bianchini C, Verso M, Mandala M, Cavanna L, Barni S, Labianca R, Buzzi F, Scambia G, Passalacqua R, Ricci S, Gasparini G, Lorusso V, Bonizzoni E, Tonato M; PROTECHT Investigators. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 2009; 10: 943–9. Haas SK, Freund M, Heigener D, Heilmann L, Kemkes-Matthes B, von Templehoff GF, Melzer N, Kakkar AK; TOPIC Investigators. Low-molecular-weight heparin versus placebo for the prevention of venous thromboembolism in metastatic breast cancer or stage III/IV lung cancer. Clin Appl Thromb Hemost 2012; 18: 159– 65. Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. N Engl J Med 2006; 355: 809–17.
Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH: reply J . T H A C H I L , * A . F A L A N G A , † M . L E V I , ‡ H . L I E B M A N § and M . D I N I S I O ¶ * * *Department of Haematology, Manchester Royal Infirmary, Manchester, UK; †Department of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy; ‡Faculty of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; §Division of Hematology, USC Norris Cancer Hospital, Los Angeles, CA, USA; ¶Department of Medical, Oral and Biotechnological Sciences, University ‘G. D’Annunzio’ of Chieti-Pescara, Chieti, Italy; and **Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands To cite this article: Thachil J, Falanga A, Levi M, Liebman H, Di Nisio M. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH: reply. J Thromb Haemost 2015; 13: 1352–3. See also Thachil J, Falanga A, Levi M, Liebman H, Di Nisio M. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH. J Thromb Haemost 2015; 13: 671–5 and Oo TH. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH: comment. This issue, pp 1351–2.
We very much appreciate the comments made by Dr Oo about our article on the management of cancer-associated disseminated intravascular coagulation (DIC) [1]. Although we agree with the author that patients with subCorrespondence: Jecko Thachil, Department of Haematology, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. Tel.: +44 161 276 4812; fax: +44 161 276 8085. E-mail: [email protected] DOI: 10.1111/jth.12962
clinical DIC are at risk of hemorrhage only, thrombosis only, or both thrombosis and hemorrhage, we believe that, in the absence of overt bleeding or factors that increase bleeding risks, the unregulated thrombin generation in this situation needs to be curtailed by prophylactic-dose anticoagulation. We also agree that there are no randomized control studies in this setting (hence this guidance document), but malignancies by themselves constitute a major risk factor for thrombosis. Therefore, subclinical evidence for excess thrombin generation should persuade physicians to consider thromboprophylaxis in these patients. This is in keeping with the four guidelines published on the management of thrombotic risk in patients with malignancies, © 2015 International Society on Thrombosis and Haemostasis
Letters to the Editor 1353
which endorse venous thromboembolism (VTE) prophylaxis with unfractionated or low molecular weight heparins or fondaparinux in all hospitalized, surgical and non-surgical cancer patients, unless contraindicated [2–5]. In addition, there is clear evidence for high D-dimer levels, which constitute a biomarker for coagulation activation, being associated with poor overall survival and increased mortality risk in cancer patients in the Vienna Cancer and Thrombosis Study [6]. There is also an increased awareness of the higher incidence of asymptomatic VTE in cancer patients, which is clinically relevant [7]. The importance of treating these incidental thromboembolic episodes with anticoagulation to prevent a worse outcome has been stressed by the recently published ISTH guidance document [8]. There are no definite data yet on thromboprophylaxis in the ambulatory setting or, for that matter, in association with subclinical DIC (a concept proposed by the guidance document). Although watchful waiting may be a reasonable strategy in ambulatory cancer patients considered to be at lower risk of thrombosis [4], we believe that hospital inpatients and high-risk ambulatory patients with subclinical DIC in association with cancer should be managed with heparin prophylaxis. This strategy should be individualized and follow a clear discussion about the need for heparin prophylaxis, taking into consideration the bleeding risks with the treatment and of the patient, the type, location and chemosensitivity of the cancer, and the practicalities of administration and cost. We also sincerely hope that randomized trials in this regard will guide us in the future. Disclosure of Conflict of Interests M. Di Nisio has received consulting fees from Bayer Health Care and Grifols, outside the submitted work. The other authors state that they have no conflict of interest.
© 2015 International Society on Thrombosis and Haemostasis
References 1 Oo TH. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH: comment. J Thromb Haemost 2015; 13: 1351–2. 2 Streiff MB, National Comprehensive Cancer Center Network. The National Comprehensive Cancer Center Network (NCCN) guidelines on the management of venous thromboembolism in cancer patients. Thromb Res 2010; 125(Suppl. 2): S128–33. 3 Mandala M, Falanga A, Roila F; ESMO Guidelines Working Group. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2011; 22(Suppl. 6): vi85–92. 4 Lyman GH, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, Clarke JM, Flowers CR, Francis CW, Gates LE, Kakkar AK, Key NS, Levine MN, Liebman HA, Tempero MA, Wong SL, Prestrud AA, Falanga A; American Society of Clinical Oncology Clinical Practice. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 31: 2189–204. 5 Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, Brilhante D, Falanga A, Gerotzafias GT, Haim N, Kakkar AK, Khorana AA, Lecumberri R, Mandala M, Marty M, Monreal M, Mousa SA, Noble S, Pabinger I, Prandoni P, et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost 2013; 11: 56–70. 6 Ay C, Dunkler D, Pirker R, Thaler J, Quehenberger P, Wagner O, Zielinski C, Pabinger I. High D-dimer levels are associated with poor prognosis in cancer patients. Haematologica 2012; 97: 1158–64. 7 Dentali F, Ageno W, Becattini C, Galli L, Gianni M, Riva N, Imberti D, Squizzato A, Venco A, Agnelli G. Prevalence and clinical history of incidental, asymptomatic pulmonary embolism: a meta-analysis. Thromb Res 2010; 125: 518–22. 8 Di Nisio M, Lee AY, Carrier M, Liebman HA, Khorana AA; The Subcommittee on Haemostasis & Malignancy. Diagnosis and treatment of incidental venous thromboembolism in cancer patients: guidance from the SSC of the ISTH. J Thromb Haemost 2015; 13: 880–3.
heparin prophylaxis, we should adopt the policy of ‘Primum non nocere (First, do no harm)’ and we should wait and watch patients closely in the management of cancerassociated sDIC, especially those with chemosensitive tumors who are receiving antineoplastic therapy. I would like the authors to reconsider their recommendation regarding heparin prophylaxis in sDIC.
4
5
Disclosure of Conflict of Interests The author states that he has no conflict of interest. References 1 Thachil J, Falanga A, Levi M, Liebman H, Di Nisio M. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH. J Thromb Haemost 2015; 13: 671–5. 2 http://www.gpnotebook.co.uk/simplepage.cfm?ID=-1154154493. Accessed 25 February 2015 3 Perry JR, Julian JA, Laperriere NJ, Geerts W, Agnelli G, Rogers LR, Malkin MG, Sawaya R, Baker R, Falanga A, Parpia S,
6
7
Finch T, Levine MN. PRODIGE: a randomized placebocontrolled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost 2010; 8: 1959–65. Agnelli G, George DJ, Kakkar AK, Fisher W, Lassen MR, Mismetti P, Mouret P, Chaudhari U, Lawson F, Turpie AG; SAVE-ONCO Investigators. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 2012; 366: 601–9. Agnelli G, Gussoni G, Bianchini C, Verso M, Mandala M, Cavanna L, Barni S, Labianca R, Buzzi F, Scambia G, Passalacqua R, Ricci S, Gasparini G, Lorusso V, Bonizzoni E, Tonato M; PROTECHT Investigators. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 2009; 10: 943–9. Haas SK, Freund M, Heigener D, Heilmann L, Kemkes-Matthes B, von Templehoff GF, Melzer N, Kakkar AK; TOPIC Investigators. Low-molecular-weight heparin versus placebo for the prevention of venous thromboembolism in metastatic breast cancer or stage III/IV lung cancer. Clin Appl Thromb Hemost 2012; 18: 159– 65. Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. N Engl J Med 2006; 355: 809–17.
Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH: reply J . T H A C H I L , * A . F A L A N G A , † M . L E V I , ‡ H . L I E B M A N § and M . D I N I S I O ¶ * * *Department of Haematology, Manchester Royal Infirmary, Manchester, UK; †Department of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy; ‡Faculty of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; §Division of Hematology, USC Norris Cancer Hospital, Los Angeles, CA, USA; ¶Department of Medical, Oral and Biotechnological Sciences, University ‘G. D’Annunzio’ of Chieti-Pescara, Chieti, Italy; and **Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands To cite this article: Thachil J, Falanga A, Levi M, Liebman H, Di Nisio M. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH: reply. J Thromb Haemost 2015; 13: 1352–3. See also Thachil J, Falanga A, Levi M, Liebman H, Di Nisio M. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH. J Thromb Haemost 2015; 13: 671–5 and Oo TH. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH: comment. This issue, pp 1351–2.
We very much appreciate the comments made by Dr Oo about our article on the management of cancer-associated disseminated intravascular coagulation (DIC) [1]. Although we agree with the author that patients with subCorrespondence: Jecko Thachil, Department of Haematology, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. Tel.: +44 161 276 4812; fax: +44 161 276 8085. E-mail: [email protected] DOI: 10.1111/jth.12962
clinical DIC are at risk of hemorrhage only, thrombosis only, or both thrombosis and hemorrhage, we believe that, in the absence of overt bleeding or factors that increase bleeding risks, the unregulated thrombin generation in this situation needs to be curtailed by prophylactic-dose anticoagulation. We also agree that there are no randomized control studies in this setting (hence this guidance document), but malignancies by themselves constitute a major risk factor for thrombosis. Therefore, subclinical evidence for excess thrombin generation should persuade physicians to consider thromboprophylaxis in these patients. This is in keeping with the four guidelines published on the management of thrombotic risk in patients with malignancies, © 2015 International Society on Thrombosis and Haemostasis
Letters to the Editor 1353
which endorse venous thromboembolism (VTE) prophylaxis with unfractionated or low molecular weight heparins or fondaparinux in all hospitalized, surgical and non-surgical cancer patients, unless contraindicated [2–5]. In addition, there is clear evidence for high D-dimer levels, which constitute a biomarker for coagulation activation, being associated with poor overall survival and increased mortality risk in cancer patients in the Vienna Cancer and Thrombosis Study [6]. There is also an increased awareness of the higher incidence of asymptomatic VTE in cancer patients, which is clinically relevant [7]. The importance of treating these incidental thromboembolic episodes with anticoagulation to prevent a worse outcome has been stressed by the recently published ISTH guidance document [8]. There are no definite data yet on thromboprophylaxis in the ambulatory setting or, for that matter, in association with subclinical DIC (a concept proposed by the guidance document). Although watchful waiting may be a reasonable strategy in ambulatory cancer patients considered to be at lower risk of thrombosis [4], we believe that hospital inpatients and high-risk ambulatory patients with subclinical DIC in association with cancer should be managed with heparin prophylaxis. This strategy should be individualized and follow a clear discussion about the need for heparin prophylaxis, taking into consideration the bleeding risks with the treatment and of the patient, the type, location and chemosensitivity of the cancer, and the practicalities of administration and cost. We also sincerely hope that randomized trials in this regard will guide us in the future. Disclosure of Conflict of Interests M. Di Nisio has received consulting fees from Bayer Health Care and Grifols, outside the submitted work. The other authors state that they have no conflict of interest.
© 2015 International Society on Thrombosis and Haemostasis
References 1 Oo TH. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH: comment. J Thromb Haemost 2015; 13: 1351–2. 2 Streiff MB, National Comprehensive Cancer Center Network. The National Comprehensive Cancer Center Network (NCCN) guidelines on the management of venous thromboembolism in cancer patients. Thromb Res 2010; 125(Suppl. 2): S128–33. 3 Mandala M, Falanga A, Roila F; ESMO Guidelines Working Group. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2011; 22(Suppl. 6): vi85–92. 4 Lyman GH, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, Clarke JM, Flowers CR, Francis CW, Gates LE, Kakkar AK, Key NS, Levine MN, Liebman HA, Tempero MA, Wong SL, Prestrud AA, Falanga A; American Society of Clinical Oncology Clinical Practice. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 31: 2189–204. 5 Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, Brilhante D, Falanga A, Gerotzafias GT, Haim N, Kakkar AK, Khorana AA, Lecumberri R, Mandala M, Marty M, Monreal M, Mousa SA, Noble S, Pabinger I, Prandoni P, et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost 2013; 11: 56–70. 6 Ay C, Dunkler D, Pirker R, Thaler J, Quehenberger P, Wagner O, Zielinski C, Pabinger I. High D-dimer levels are associated with poor prognosis in cancer patients. Haematologica 2012; 97: 1158–64. 7 Dentali F, Ageno W, Becattini C, Galli L, Gianni M, Riva N, Imberti D, Squizzato A, Venco A, Agnelli G. Prevalence and clinical history of incidental, asymptomatic pulmonary embolism: a meta-analysis. Thromb Res 2010; 125: 518–22. 8 Di Nisio M, Lee AY, Carrier M, Liebman HA, Khorana AA; The Subcommittee on Haemostasis & Malignancy. Diagnosis and treatment of incidental venous thromboembolism in cancer patients: guidance from the SSC of the ISTH. J Thromb Haemost 2015; 13: 880–3.
