Journal of Thrombosis and Haemostasis, 13: 1351–1353
LETTERS TO THE EDITOR
Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH: comment T. H. OO The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA To cite this article: Oo TH. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH: comment. J Thromb Haemost 2015; 13: 1351–2. 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 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. This issue, pp 1352–3.
I read with interest the recent article by Thachil et al. [1]. Although I congratulate Dr Thachil and his colleagues for this article, I would like to make some comments. While I agree with the authors’ classification of cancerassociated disseminated intravascular coagulation (DIC) into procoagulant, hyperfibrinolytic and subclinical types and their recommendations on the treatment of procoagulant DIC and hyperfibrinolytic DIC, I have strong reservations on the treatment of subclinical DIC (sDIC). In the article, the authors stated that ‘subclinical types of DIC will also benefit from heparin prophylaxis’ and they recommended ‘prophylactic anticoagulation in all types with cancer-related DIC, except hyperfibrinolytic DIC, in the absence of contraindications’. DIC is an intermediary mechanism of disease and it signifies an ongoing tug-of-war between hemorrhage and thrombosis in the clinical sense. Conceptually, the sDIC is almost an equilibrium state where the amounts of thrombin and plasmin generated do not cause hemorrhage or thrombosis clinically but are manifested by the laboratory markers of coagulation and activation of fibrinolysis. The direction where the sDIC will go eventually is uncertain. Over time, the sDIC may progress into hemorrhage only or thrombosis only or both thrombosis and hemorrhage or the laboratory parameters of sDIC may improve upon the initiation of antineoplastic therapy such Correspondence: Thein Hlaing Oo, The University of Texas M.D. Anderson Cancer Center, Section of Thrombosis and Benign Hematology (Unit 1464), 1515 Holcombe Blvd., Houston, TX 77030, USA. Tel.: +1 713 563 4260; fax: +1 713 563 4443. E-mail: [email protected] DOI: 10.1111/jth.12904 Received 26 February 2015 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 11 March 2015 © 2015 International Society on Thrombosis and Haemostasis
as chemotherapy. Alternatively, the cancer patient may simply die with sDIC but not of it. As a consultant hematologist-oncologist at a major cancer treatment and research center, I frequently encounter several cases of sDIC in routine clinical practice. As the sDIC is subclinical in nature, in my opinion, there is no routine need to provide heparin prophylaxis to the patients in many cases. Many neoplasms such as lymphomas, germ cell tumors, small cell lung cancer, some sarcomas, breast cancer, ovarian cancer and prostate cancer are responsive to chemotherapy and/or hormonal therapy [2]. Most of the time, with the achievement of response of such tumors to antineoplastic therapy, the improvement in the laboratory parameters of sDIC can be observed even without heparin prophylaxis. Although this phenomenon sounds anecdotal, I usually wait and watch those cancer patients with sDIC closely while cancer is being actively treated with antineoplastic therapy. It is important to note that the efficacy and safety of heparin prophylaxis in DIC has never been studied in sound clinical studies and the data are even scarcer in sDIC. Even though it sounds rational to partly inhibit thrombin generation by heparin, there are no randomized controlled trials demonstrating that routine heparin use in sDIC results in an improvement of clinically relevant outcomes. Certain things are clear with long-term ambulatory heparin prophylaxis, such as the high cost of low-molecular-weight heparins, patient discomfort, a trend toward increased intracranial bleeding in patients with gliomas [3], heparinassociated clinically relevant bleeding risks of 2.8% to 16.7% [4–6], and risk of heparin-induced thrombocytopenia of 0.1 to 5% [7]. There are also unknowns such as unknown duration and unclear benefits. Therefore, I strongly believe that watchful waiting has a role in the management of cancer-associated sDIC. There is a chance that antineoplastic therapy will improve the laboratory parameters of sDIC without heparin prophylaxis, especially in chemosensitive tumors. Given the unclear benefits in this setting and known potential side-effects of
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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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
Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH: comment T. H. OO The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA To cite this article: Oo TH. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH: comment. J Thromb Haemost 2015; 13: 1351–2. 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 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. This issue, pp 1352–3.
I read with interest the recent article by Thachil et al. [1]. Although I congratulate Dr Thachil and his colleagues for this article, I would like to make some comments. While I agree with the authors’ classification of cancerassociated disseminated intravascular coagulation (DIC) into procoagulant, hyperfibrinolytic and subclinical types and their recommendations on the treatment of procoagulant DIC and hyperfibrinolytic DIC, I have strong reservations on the treatment of subclinical DIC (sDIC). In the article, the authors stated that ‘subclinical types of DIC will also benefit from heparin prophylaxis’ and they recommended ‘prophylactic anticoagulation in all types with cancer-related DIC, except hyperfibrinolytic DIC, in the absence of contraindications’. DIC is an intermediary mechanism of disease and it signifies an ongoing tug-of-war between hemorrhage and thrombosis in the clinical sense. Conceptually, the sDIC is almost an equilibrium state where the amounts of thrombin and plasmin generated do not cause hemorrhage or thrombosis clinically but are manifested by the laboratory markers of coagulation and activation of fibrinolysis. The direction where the sDIC will go eventually is uncertain. Over time, the sDIC may progress into hemorrhage only or thrombosis only or both thrombosis and hemorrhage or the laboratory parameters of sDIC may improve upon the initiation of antineoplastic therapy such Correspondence: Thein Hlaing Oo, The University of Texas M.D. Anderson Cancer Center, Section of Thrombosis and Benign Hematology (Unit 1464), 1515 Holcombe Blvd., Houston, TX 77030, USA. Tel.: +1 713 563 4260; fax: +1 713 563 4443. E-mail: [email protected] DOI: 10.1111/jth.12904 Received 26 February 2015 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 11 March 2015 © 2015 International Society on Thrombosis and Haemostasis
as chemotherapy. Alternatively, the cancer patient may simply die with sDIC but not of it. As a consultant hematologist-oncologist at a major cancer treatment and research center, I frequently encounter several cases of sDIC in routine clinical practice. As the sDIC is subclinical in nature, in my opinion, there is no routine need to provide heparin prophylaxis to the patients in many cases. Many neoplasms such as lymphomas, germ cell tumors, small cell lung cancer, some sarcomas, breast cancer, ovarian cancer and prostate cancer are responsive to chemotherapy and/or hormonal therapy [2]. Most of the time, with the achievement of response of such tumors to antineoplastic therapy, the improvement in the laboratory parameters of sDIC can be observed even without heparin prophylaxis. Although this phenomenon sounds anecdotal, I usually wait and watch those cancer patients with sDIC closely while cancer is being actively treated with antineoplastic therapy. It is important to note that the efficacy and safety of heparin prophylaxis in DIC has never been studied in sound clinical studies and the data are even scarcer in sDIC. Even though it sounds rational to partly inhibit thrombin generation by heparin, there are no randomized controlled trials demonstrating that routine heparin use in sDIC results in an improvement of clinically relevant outcomes. Certain things are clear with long-term ambulatory heparin prophylaxis, such as the high cost of low-molecular-weight heparins, patient discomfort, a trend toward increased intracranial bleeding in patients with gliomas [3], heparinassociated clinically relevant bleeding risks of 2.8% to 16.7% [4–6], and risk of heparin-induced thrombocytopenia of 0.1 to 5% [7]. There are also unknowns such as unknown duration and unclear benefits. Therefore, I strongly believe that watchful waiting has a role in the management of cancer-associated sDIC. There is a chance that antineoplastic therapy will improve the laboratory parameters of sDIC without heparin prophylaxis, especially in chemosensitive tumors. Given the unclear benefits in this setting and known potential side-effects of
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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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
