590 Letters to the Editor
The interesting results of Cao and Long Zheng suggest that conformationally activated ADAMTS-13 may have more than one role in the fibrinolytic pathway, potentially inducing plasminogen activation as well as altering the susceptibility of fibrin(ogen) to t-PA/plasmin lysis through its direct proteolysis of the Aa chain. Disclosure of Conflict of Interests The authors state that they have no conflict of interest.
References 1 South K, Freitas MO, Lane DA. Conformational quiescence of ADAMTS-13 prevents proteolytic promiscuity. J Thromb Haemost 2016; 14: 2011–22. 2 South K, Luken BM, Crawley JT, Phillips R, Thomas M, Collins RF, Deforche L, Vanhoorelbeke K, Lane DA. Conformational activation of ADAMTS13. Proc Natl Acad Sci USA 2014; 111: 18578–83. 3 Muia J, Zhu J, Gupta G, Haberichter SL, Friedman KD, Feys HB, Deforche L, Vanhoorelbeke K, Westfield LA, Roth R, Tolia NH, Heuser JE, Sadler JE. Allosteric activation of ADAMTS13 by von Willebrand factor. Proc Natl Acad Sci USA 2014; 111: 18584–9.
Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer: comment S . N O B L E , * R . A L I K H A N , † A . R O B B I N S , ‡ F . M A C B E T H * and K . H O O D * *Cardiff University; †University Hospital of Wales, Cardiff; and ‡West Middlesex Hospital, London, UK
To cite this article: Noble S, Alikhan R, Robbins A, Macbeth F, Hood K. Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer: comment. J Thromb Haemost 2017; 15: 590–1. See also Mansfield AS, Tafur AJ, Wang CE, Kourelis TV, Wysokinska EM, Yang P. Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer. J Thromb Haemost 2017; 14: 1773–8 and Mansfield AS, Tafur AJ. Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer: reply. This issue, pp 591–2.
We read with interest the article by Mansfield et al. [1] in which the authors report their attempt to validate the Khorana Risk Score (KRS) [2] in the prediction of venous thromboembolism (VTE) among ambulant patients with lung cancer receiving chemotherapy. In their prospectively collected lung cancer database of 719 patients, there were 83 (11.5%) episodes of VTE. The incidence of VTE for a high-risk KRS (≥ 3) was 12.4%, and that for an intermediate-risk KRS (1–2) was 12.1%. The findings of Mansfield et al. [1] are consistent with the results from a subgroup analysis of patients receiving chemotherapy in the FRAGMATIC study, which were presented at the XXV ISTH Congress [3]. In brief, Correspondence: Simon Noble, Cardiff University – Palliative Medicine, Royal Gwent Hospital Cardiff Rd, Newport, NP20 2UB, Cardiff, UK. Tel.: +44 16 3323 4234; fax: +44 16 3365 6063. E-mail:
[email protected] DOI: 10.1111/jth.13594 Received 24 November 2016, Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 2 December 2016
patients with primary bronchial carcinoma, non-small-cell lung cancer or small-cell lung cancer within 6 weeks of diagnosis and prior to definitive anticancer treatment were enrolled in the FRAGMATIC study: a phase III trial investigating the impact on overall survival of adding low molecular weight heparin to usual care in patients with lung cancer [4]. Patients were randomized in a 1 : 1 ratio to receive either dalteparin 5000 IU daily for 24 weeks, or no dalteparin (control group). All patients were riskassessed with the KRS. The addition of dalteparin had no impact on overall survival, but did reduce the risk of VTE from 9.7% to 5.5% (hazard ratio 0.57; 95% confidence interval 0.42–0.79, P = 0.0005) in the dalteparin arm, with no difference in major bleeding. However, there was an increased rate of major plus clinically relevant non-major bleeding (CRNMB) (5.6% versus 1.3%). In the control group of 910 lung cancer patients receiving chemotherapy, 108 (11.9%) developed VTE, which is a similar number of events to those described by Mansfield et al. [1]. The rate of VTE for a high-risk KRS (≥ 3) was 29/246 (11.8%), and those for an intermediate-risk KRS (1–2) were 44/342 (12.9%) and 35/322 (10.9%), respectively. When the intermediate-risk to high-risk group (score of ≥ 3) cut-off point was used, within the control group, the KRS had a sensitivity (proportion of participants who had a VTE assigned to the high-risk group) of 21.43%, a
© 2016 International Society on Thrombosis and Haemostasis
Letters to the Editor 591
specificity (proportion of participants who did not have a VTE assigned to the intermediate-risk group) of 72.80%, a negative predictive value (probability of no VTE occurring in those assigned to the intermediate-risk group) of 89.46%, and a positive predictive value (probability of a VTE occurring in those assigned to the high-risk group) of 7.92%. In a large population of patients with lung cancer, the current components of the KRS, namely the primary site of cancer, platelet count, hemoglobin level and/or use of erythropoiesis-stimulating agents, leukocyte count, and body mass index, were unable to discriminate between patients at high or low risk of VTE. We agree with Mansfield et al. [1] that there is a need to develop cancer-specific risk assessment tools for the prediction of VTE and to help guide targeted thromboprophylaxis. There is a particular need for such a tool to be developed for patients with lung cancer, a common malignancy that has a clinically significant risk of chemotherapy-associated VTE but an unacceptable major/CRNMB rate when pharmacologic prophylaxis is applied to all. A pooled analysis of data from Mansfield et al., the FRAGMATIC study and other relevant studies is arguably the next practical step in developing a clinically applicable lung cancer risk assessment tool. We welcome the opportunity to pool our data to achieve this common goal. Addendum
Disclosure of Conflict of Interests S. Noble reports receiving grants from Pfizer, during the conduct of the study; personal fees from Pfizer and Boheringer Ingelheim; and grants and personal fees from Leo Pharma, outside the submitted work. R. Alikhan reports receiving personal fees from Pfizer, Leo Pharma, Bristol-Myers Squibb, Boheringer Ingelheim, and Daiichi, outside the submitted work. K. Hood and F. Macbeth report receiving grants from Pfizer, during the conduct of the study. References 1 Mansfield AS, Tafur AJ, Wang CE, Kourelis TV, Wysokinska EM, Yang P. Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer. J Thromb Haemost 2016; 14: 1773–8. 2 Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111: 4902–7. 3 Noble S, Robbins A, Alikhan R, Macbeth F, Hood K. Prediction of venous thromboembolism in lung cancer patients receiving chemotherapy. J Thromb Haemost 2015; 13(Suppl. 2): 143. OR130. 4 Macbeth F, Noble S, Evans J, Ahmed S, Cohen D, Hood K, Knoyle D, Lianne S, Longo M, Moore B, Woll P, Appel W, Dickson J, Ferry D, Brammer C, Griffiths G. Randomized phase III trial of standard therapy plus low molecular weight heparin in patients with lung cancer: FRAGMATIC trial. J Clin Oncol 2015; 34: 488–94.
S. Noble and R. Alikhan drafted the manuscript. A. Robbins undertook the initial data analysis. The other authors critically revised the manuscript.
Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer: reply A. S. MANSFIELD*
and A . J . T A F U R † ‡
*Department of Oncology, Division of Medical Oncology, Mayo Clinic, Rochester, MN; †Department of Medicine, Division of Cardiology – Vascular Medicine Program, NorthShore University Health System, Evanston, IL; and ‡School of Medicine, University of Chicago, Chicago, IL, USA
To cite this article: Mansfield AS, Tafur AJ. Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer: reply. J Thromb Haemost 2017; 15: 591–2. See also Mansfield AS, Tafur AJ, Wang CE, Kourelis TV, Wysokinska EM, Yang P. Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer. J Thromb Haemost 2017; 14: 1773–8 and Noble S, Alikhan R, Robbins A, Macbeth F, Hood K. Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer: comment. This issue, pp 590–1.
© 2016 International Society on Thrombosis and Haemostasis
