Incidence and risk factors for developing venous thromboembolism in Japanese with diffuse large b-cell lymphoma

Thrombosis Research 130 (2012) 7–11

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Incidence and risk factors for developing venous thromboembolism in Japanese with diffuse large b-cell lymphoma ☆ Kenji Yokoyama a,⁎, Mitsuru Murata b, Yasuo Ikeda c, Shinichiro Okamoto a a b c

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan Major in Life Science and Medical Bioscience Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan

a r t i c l e

i n f o

Article history: Received 15 June 2011 Received in revised form 30 August 2011 Accepted 20 September 2011 Available online 15 October 2011 Keywords: Venous thromboembolism Lymphoma Japanese Performance status

a b s t r a c t The reported incidence of venous thromboembolism (VTE) in lymphoma patients is 5% to 17% in Western countries. The incidence and risk factors for developing VTE, however, are not well elucidated in Asian lymphoma patients. The incidence and clinical presentations of VTE were retrospectively assessed in 142 patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL) from April 2006 to November 2010 at Keio University Hospital. Clinical data were collected and all episodes of symptomatic VTE confirmed by imaging were included. Patients with primary central nervous system lymphoma or DLBCL transformed from prior low-grade lymphoma were excluded. Fifteen (11%) patients had at least one episode of VTE. Five patients developed VTE before beginning chemotherapy and 8 episodes of VTE occurred during the first three cycles of chemotherapy. By univariate analysis, age 60 or over (odds ratio [OR] 4.81, confidence interval [CI] 1.04-22.20, p = 0.04), Eastern Cooperative Oncology Group performance status 2, 3, or 4 (OR 39.90, CI 5.05-315.20, p = 0.0005), and International Prognostic Index high or high-intermediate (OR 9.40, CI 1.20-73.69, p = 0.03) were identified as risk factors for developing VTE. By multivariate analysis, performance status 2, 3, or 4 remained a significant risk factor for developing VTE (OR 31.14, CI 3.79-255.62, p = 0.001). The incidence of VTE in Japanese with DLBCL was comparable with that in the Western population. Patients with DLBCL and poor performance status at diagnosis were at high risk for developing VTE especially early in the course of treatment. © 2011 Elsevier Ltd. All rights reserved.

Introduction Venous thromboembolism (VTE) is a common and serious complication in patients with cancer [1-3], causing significant morbidity and mortality [4,5]. Patients with cancer have a several-fold increased risk for developing VTE compared to the general population, but the incidence of VTE varies according to the type of cancer. A higher incidence of VTE in patients with pancreas, stomach, brain, ovary, kidney, or lung cancer, and patients with metastatic cancer is well documented [1,6-10]. Recent studies demonstrated a higher incidence of VTE in patients with hematologic malignancies as well, especially in those

Abbreviations: VTE, venous thromboembolism; DLBCL, diffuse large B cell lymphoma; DVT, deep vein thrombosis; PE, pulmonary embolism; NVT, neck vein thrombosis; PS, performance status; LDH, lactate dehydrogenase; IPI, International Prognostic Index; ECOG, Eastern Cooperative Oncology Group; CVC, central venous catheter; VKA, vitamin K antagonists; UFH, unfractionated heparin; LMWH, low molecular weight heparin. ☆ This manuscript was presented at XXIII Congress of the International Society on Thrombosis and Haemostasis (Kyoto, Japan, July 23–28, 2011). ⁎ Corresponding author at: Keio University, School of Medicine, Department of Medicine, Division of Hematology, 35 Shinano-machi, Shinjuku-ku, Tokyo 160–8582, Japan. Tel.: +81 3 3353 1211x62385; fax: +81 3 3353 3515. E-mail address: [email protected] (K. Yokoyama). 0049-3848/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2011.09.022

with lymphoma, and the reported incidence of VTE in patients with lymphoma ranges from 5% to 17% [9,11-14]. The incidence of VTE is even higher in patients with a particular type of lymphoma, such as primary central nervous system lymphoma [15] or mediastinal large B-cell lymphoma [16], indicating that thromboprophylaxis might be beneficial for cohorts at high risk for developing VTE in lymphoma. The previous studies were mainly conducted in Western countries, however, and might not be applicable for Asians or Japanese. Several studies reported that the incidence of VTE in Asians is lower than that in the Western population [17,18]. Studies conducted in the United States also demonstrate that the risk for both idiopathic and secondary VTE in Asians is approximately one-fifth to half that in whites [19,20]. On the other hand, increased mortality from pulmonary embolism (PE) was recently reported in the Japanese [21], and recent prospective studies demonstrate that the incidence of VTE in Japanese patients that have undergone high-risk orthopedic or major abdominal surgery is comparable to that in the Western population [22,23]. With regard to VTE observed in cancer, several studies suggest that the frequency of VTE in Asian patients with pancreatic cancer or myeloma is lower than that in the Western population [24-26]. The association of VTE with cancer has not been fully elucidated in Asians, however, and few data are available regarding the incidence or clinical presentations of VTE in Japanese patients with lymphoma. Therefore, we conducted a

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retrospective analysis to clarify the incidence of VTE and risk factors for developing VTE in Japanese patients with lymphoma.

analysis. Statistical analyses were performed using StatView (ver 5). A p value of less than 0.05 was considered statistically significant.

Methods

Results

Study population

Patient characteristics

162 Patients newly with diagnosed diffuse large B-cell lymphoma (DLBCL) at Keio University Hospital from April 2006 to November 2010 were identified from our database, and those with a confirmed pathologic diagnosis of DLBCL (World Health Organization classification) who received the first cycle of chemotherapy at Keio University Hospital were included in this study. Patients who were diagnosed at other institutes and referred to our hospital before commencing the first cycle of chemotherapy were included if the diagnosis of DLBCL was reconfirmed at our institute based on a review of pathologic specimens. 5 patients who received at least one cycle of chemotherapy at another institute were excluded. Those with primary central nervous system lymphoma (2 patients) or DLBCL transformed from prior low-grade lymphoma (13 patients) were excluded from this study. Thus, 142 patients were selected as a cohort for assessing the incidence of VTE.

The characteristics of 142 patients included in this study are shown in Table 1. Laboratory values were documented at the timepoint of diagnosis. Of these, 15 (11%) patients had an episode of VTE. The median age of patients was 63 years and more than 60% of the patients were 60 years of age or older. More than 60% of the patients had advanced stage (III or IV) disease. A CVC was inserted in 25% of the patients during chemotherapy. R-CHOP/D (R: rituximab, C: cyclophosphamide, H: doxorubicin, O: vincristine, P: prednisolone, D: dexamethasone) was used as the initial chemotherapy for most of the patients. Six (4.2%) patients were treated with R-Hyper-C-VAD/R-MTX-Ara-C (V: vincristine, A: doxorubicin, D: dexamethasone, MTX: methotrexate), and six (4.2%) patients were treated with other regimens; CHOP for two, rituximab monotherapy for two, MTX-Ara-C for one, and R-ESHAP (E: etoposide, S: methylprednisolone, HA: high dose Ara-C, P: cisplatinum) for one. Responses to the first regimen of chemotherapy could not be evaluated in 27 patients who were on treatment at the time of analysis, or were transferred to other hospitals before completion of the initial chemotherapy. Complete remission was achieved in 82 (71.3%) of 115 evaluable patients. None of the patients had prior VTE, but 2 patients were on thrombophylaxis with vitamin K antagonists (VKA) for cardiac indications at the time of diagnosis of DLBCL(Table 1).

Definition and risk factors for developing VTE Lymphoma patients with symptoms such as localized tenderness along the distribution of deep venous system, entire leg swelling, unilateral calf swelling, pitting edema confined to the unilateral leg, collateral superficial veins, chest pain, tachycardia, hypoxia, or hemoptysis were suspected to have VTE and diagnostic imaging was performed. Deep vein thrombosis (DVT) of the lower extremity was confirmed by ultrasound. Pulmonary embolism (PE) and neck vein thrombosis (NVT) were confirmed by spiral computer tomography. VTE in this study was defined as an episode of VTE with those symptoms (symptomatic VTE) confirmed by diagnostic imaging. The data collected at diagnosis included the patient's sex, age, body mass index, performance status (PS), disease stage, serum lactate dehydrogenase (LDH), white blood cell count, hemoglobin level, platelet count, numbers of extranodal sites, International Prognostic Index (IPI) score, and the presence of B symptoms. Anemia and thrombocytosis were defined as hemoglobin level below 10 g/dl and platelet count of at least 350 × 10 9 /L according to the previous report developing a predictive model for chemotherapy-associated thrombosis [27]. PS was evaluated by the definition of the Eastern Cooperative Oncology Group (ECOG). Data regarding the chemotherapy regimens, including the dose and administration schedule of agents used, and the response to chemotherapy were also obtained. Known risk factors for VTE: the placement of central venous catheter (CVC), recent major surgery, recent bone fracture of the hip or leg, prior history of VTE, and use of prophylactic anticoagulants at diagnosis were also recorded. Placement of CVC was counted when the CVC was inserted at least once during or between the cycles of chemotherapy regardless of the duration of placement. If the CVC was inserted for the first time after the occurrence of VTE or after the completion of chemotherapy, it was not counted. Screening for inherited thrombophilia was performed only in patients with VTE.

Fifteen episodes of VTE occurred in this study population. Thirteen patients had DVT of the lower extremity and 2 of them also had PE, but none of these was life-threatening. Two patients had NVT (Table 2). Five (33.3%) episodes of VTE, 2 of them before the final diagnosis of DLBCL and 3 of them at staging, were diagnosed before the beginning of the first cycle of chemotherapy, 4 (26.7%) episodes occurred during or following the first cycle of chemotherapy, and only 2 (13.3%) episodes occurred after completion of the first regimen of chemotherapy (Fig. 1). Venous compression caused by intra-abdominal or intra-pelvic lymphoma masses was radiographically demonstrated in four patients with VTE. Three patients with VTE were bedridden because of paralysis of the lower extremities due to compression of the spinal nerve by a vertebral mass (2 patients) and hip fracture (1 patient). Two episodes of NVT occurred at the site of the CVC placement. After admission to the hematology ward, all but five patients that already had VTE were encouraged to move about and received physical therapy if needed. Of the 15 patients developing VTE, 12 were treated with anticoagulants. Eight patients were treated with dose-adjusted unfractionated heparin (UFH), three patients started on VKA, and one who had already received VKA at the time of the diagnosis of VTE continued VKA without additional anticoagulants thereafter. Although one of the patients discontinued VKA because of major gastrointestinal bleeding, others continued anticoagulant treatment without significant bleeding episodes. Three patients received no anticoagulants, even after developing VTE. Recurrence of symptomatic VTE was not observed in any of the patients with VTE regardless of the use of anticoagulants.

Statistical analysis

Risk factors for developing VTE

To identify risk factors for developing VTE in patients with DLBCL, univariate and multivariate logistic regression analyses were performed. Univariate analysis was conducted on the potential risk factors for developing VTE: clinical characteristics and laboratory values at diagnosis, then considering the sample size and number of variables, variables with p value of 0.05 or less were selected for multivariate logistic regression

The association between the occurrence of VTE and patient characteristics and values at diagnosis were analyzed by univariate logistic regression analysis. Age 60 or older (odds ratio [OR] 4.81, confidence interval [CI] 1.04-22.20, p = 0.04), ECOG PS 2, 3, or 4 (OR 39.90, CI 5.05-315.20, p = 0.0005) and IPI score high or high-intermediate (OR 9.40, CI 1.20-73.69, p = 0.03) were identified as significant risk factors

Clinical presentations and management of VTE

K. Yokoyama et al. / Thrombosis Research 130 (2012) 7–11

Sex Male Female Age Mean ± SD b 60 ≥ 60 BMI (kg/m2) Mean ± SD b 25 ≥ 25 ECOG PS 0-1 2 3 4 Stage I II III IV Serum LDH (IU/L) Mean ± SD Normal (≤ 210) Above normal White blood cell count (/cmm) Mean ± SD Hemoglobin (g/dl) Mean ± SD Platelet count (× 109/L) Mean ± SD Numbers of extranodal site 0-1 ≥2 IPI score L LI HI H B symptoms No Yes First regimen of chemotherapy R-CHOP/D R-Hyper-CVAD Others Responses to the first regimen* CR No CR Presence of CVC No Yes Recent major surgery, bone fracture of the leg or hip No Yes Anticoagulants at the time of diagnosis of DLBCL No Yes

Table 2 Sites of venous thromboembolism in patients with diffuse large B-cell lymphoma. VTE (+) n (%)

VTE (-) n (%)

total n (%)

7 (46.7) 8 (53.3)

77 (60.6) 50 (39.4)

84 (59.2) 58 (40.8)

69.9 ± 12.0 2 (13) 13 (86.7)

62.1 ± 12.0 53 (41.7) 74 (58.3)

63.0 ± 13.1 55 (38.7) 87 (61.3)

22.2 ± 4.4 11 (73.3) 4 (26.7)

21.9 ± 3.3 107 (84.3) 20 (15.7)

21.9 ± 3.4 118 (83.1) 24 (16.9)

1 (6.7) 10 (66.7) 2 (13.3) 2 (13.3)

94 (74.0) 29 (22.8) 1 (0.8) 3 (2.4)

95 (66.9) 39 (27.5) 4 (2.8) 4 (2.8)

1 (6.7) 1 (6.7) 3 (20.0) 10 (66.7)

17 (13.4) 21 (16.5) 16 (12.6) 73 (57.5)

18 (12.7) 22 (25.5) 19 (13.4) 83 (58.5)

774.9 ± 694.1 2 (13.3) 13 (86.7)

435.8 ± 732.4 52 (40.9) 75 (59.1)

471.6 ± 733.6 54 (38.0) 88 (62.0)

6020 ± 2040

7230 ± 5970

7100 ± 5690

10.8 ± 1.8

12.1 ± 2.1

11.9 ± 2.1

251.9 ± 90.6

239.7 ± 100.9

241.0 ± 99.6

8 (53.3) 7 (46.7)

85 (66.9) 42 (33.1)

93 (65.5) 49 (34.5)

0 (0) 1 (6.7) 3 (20.0) 11 (73.3)

26 (20.5) 25 (19.7) 42 (33.1) 34 (26.8)

26 (18.3) 26 (18.3) 45 (31.7) 45 (31.7)

11 (73.3) 4 (26.7)

91 (71.7) 36 (28.3)

102 (71.8) 40 (28.2)

15 (100) 0 (0) 0 (0)

115 (90.6) 6 (4.7) 6 (4.7)

130 (91.5) 6 (4.2) 6 (4.2)

6 (46.2) 7 (53.8)

76 (74.5) 26 (25.4)

82 (71.3) 33 (28.7)

11 (73.3) 4 (26.7)

95 (74.8) 32 (25.2)

106 (74.6) 36 (35.4)

14 (93.3) 1 (6.7)

119 (93.7) 8 (6.3)

133 (93.7) 9 (6.3)

14 (93.3) 1 (6.7)

126 (99.2) 1 (0.8)

140 (98.6) 2 (1.4)

VTE: venous thromboembolism, BMI: body mass index, ECOG: Eastern Cooperative Oncology Group, PS: performance status, LDH: lactate dehydrogenase, IPI: International Prognostic Index, L; low, LI: low-intermediate, HI: high-intermediate, H: high, R-CHOP/D: rituximab, cyclophosphamide, adriamycin, vincristine, predonine/dexamethasone, R-Hyper-CVAD: rituximab, cyclophosphamide, vincristine, adriamycin, dexamethasone, CR: complete remission, CVC: central venous catheter. * 115 patients were evaluable.

for developing VTE (p b 0.05; Table 3). In multivariate analysis, LDH level above upper normal limits (p = 0.05) was included in addition to age and ECOG PS. IPI was excluded because IPI is closely related to other variables; age, PS, and LDH. The results of the multivariate analysis

Site

Number of patients (%)

Lower extremity Lower extremity + Pulmonary Neck Total

11 2 2 15

(73.3) (13.3) (13.3) (100)

revealed that only ECOG PS 2, 3, or 4 was a significant risk factor for VTE in this study population (OD 31.14, 3.79-255.62, p = 0.001; Table 4). Deficiency of either antithrombin, protein C, or protein S was not detected in patients with VTE. Discussion Our study population differs from that in recent studies of the Western population in that our patients were older, had more advanced stage disease, and were all Japanese patients with DLBCL. Although the ethnic background of the study population was rarely documented in previous studies, less than 3% of subjects were possibly Asian in one of the studies [12], suggesting that these studies mostly represent whites. Nevertheless, the incidence of VTE in patients with DLBCL in our study was comparable to the reported incidence of VTE in the Western population [11-14]. More than half of the episodes of VTE in our study occurred before beginning, during, or early after the first cycle of chemotherapy. This finding was also comparable to the results of the other studies [12,13,16]. Known risk factors and tumor specific factors may contribute to the development of VTE in patients with lymphoma. In our study, poor performance status (ECOG PS 2, 3, or 4) was the only significant risk factor for developing VTE (OR 31.14), and this has not been identified as a risk factor in other studies [13]. Differences in the study population and chemotherapy regimens may explain this difference. In our study, more than 90% of patients with VTE had ECOG PS 2, 3, or 4, and 4 (50%) of 8 patients with ECOG PS 3 or 4 experienced VTE. Prolonged immobilization is an established risk factor for VTE in both Japanese and Western populations [28,29]. Patients who are confined to bed and have one or more additional risk factors, including active cancer or acute neurologic disease, are at an increased risk of developing VTE. Therefore, prophylactic anticoagulants are recommended for those patients according to the 8th ACCP guidelines [30]. In our patients, those with ECOG PS 3 or 4 should have received prophylactic anticoagulants. In our practice,

(%) 30

Percent of patients

Table 1 Patient Characteristics (n = 142).

9

20

10

0

Fig. 1. Timing of the Occurrence of Venous Thromboembolism (n = 15).

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Table 3 Risk factors for developing venous thromboembolism by univariate analysis.

Female Sex Age ≥ 60 BMI PS 0, 1 vs. 2, 3, 4 Stage I, II vs. III, IV LDH N normal Hb b 10 Plt N 350×109 Extranodal sites ≥ 2 IPI score HI or H Existence of B symptoms Presence of CVC Recent major surgery or bone fracture of the leg or hip

Odds Ratio

95% CI (Upper-Lower)

p Value

0.57 4.81 1.95 39.90 2.78 4.50 1.84 2.64 1.84 9.40 0.92 1.18 1.06

0.19-1.67 1.04-22.20 0.56-6.72 5.05-315.20 0.60-12.90 0.98-20.82 0.53-6.32 0.65-10.78 0.62-5.41 1.20-73.69 0.28-3.08 0.35-3.97 0.12-9.14

0.30 0.04 0.29 0.0005 0.19 0.05 0.34 0.18 0.27 0.03 0.89 0.79 0.96

CI: confidence interval, CVC: central venous catheter.

however, only 2 of 8 patients with ECOG PS 3 or 4 received VKA and prescription of VKA was not intended for preventing VTE but for cardiac indications. These practices might have contributed to the high incidence of VTE in patients with poor PS in our study. Although detailed information about the use of prophylactic anticoagulants or PS of the subjects was not described in previous studies, only 4.3% of patients were on prophylactic anticoagulants when VTE occurred in one large-scale retrospective study [13]. For VTE occurring in patients with cancer, a therapeutic dose of low molecular weight heparin (LMWH) for 5 to 10 days followed by longterm secondary prophylaxis at least for 6 months is recommended [31-33]. In our patients with VTE, 12, including two patients with VTE occurring before the final diagnosis of DLBCL, received dose-adjusted UFH or VKA and 3 were not treated with any anticoagulants. We could not use LMWH because the National Health Insurance in Japan did not cover the use of LMWH for treatment of VTE during the study period. Therefore, dose-adjusted UFH was used instead of LMWH to treat and prevent VTE recurrence. Three patients with distal small DVT of the lower extremity were thought to have very few risk factors for life-threatening PE and were placed on VKA to prevent VTE recurrence. Anticoagulants were not used in three patients because they were at extremely high risk for major bleeding; two patients had active hemorrhagic lesions of gastrointestinal lymphoma, and one patient had severe thrombocytopenia. VTE was localized to calf vein in these three patients. They were monitored closely and chemotherapy was continued. Recurrence or worsening of VTE was not observed in these three patients during chemotherapy. Although our practice did not necessarily comply with the guidelines in Western countries, no life-threatening PE or symptomatic VTE recurrence were observed in our study population. Placement of CVC is a well-known risk factor for VTE and the rate of symptomatic VTE related to the placement of CVC in patients with hematologic malignancy is 11% to 45% in the patients with CVC [14,34,35]. Although CVC placement was not a significant risk factor for VTE in our study, both episodes of NVT occurred at the site of placement and these episodes seemed to be caused by the CVC. The CVC was an important local risk factor for VTE in some patients in our study, whereas only 2 of 36 (5.6%) patients with CVC experienced VTE and the incidence was lower than that reported in previous studies. CVC was usually placed in internal jugular vein in our institute. Site

Table 4 Risk factors for developing venous thromboembolism by multivariate logistic regression analysis.

Age ≥ 60 PS 0, 1 vs. 2, 3, 4 LDH N normal

Odds Ratio

95% CI (Upper-Lower)

p Value

4.01 31.14 1.93

0.79-20.49 3.79-255.62 0.35-10.70

0.09 0.001 0.45

and duration of CVC placement or the CVC material might contribute to the low incidence of VTE in the patients with CVC in our study. Venous compression caused by local lymphoma growth was also identified as a risk factor for VTE in some studies. In one study, more than 50% of VTE was related to venous compression [16], and in another study 11% of VTE in patients with advanced stage lymphoma was related to venous compression [11]. Although the definition of venous compression was not clearly described in those studies, at least 4 (27%) of 15 episodes of VTE occurred in patients with radiographically proven venous compression by local lymphoma growth in our study. Our study has some limitations. The sample size was smaller and the follow-up period was shorter compared to similar retrospective studies recently conducted in the Western population [11-13]. An unfavorable influence of VTE on the survival was reported in some studies [12,16], but we were not able to conduct such analysis because of the above-mentioned limitations. Three episodes of asymptomatic VTE incidentally detected during staging or restaging were found by chart review, but the incidence of asymptomatic VTE was uncertain because staging or restaging radiological imaging did not examine the existence of DVT in the lower extremities. In addition, we screened for the possibility of inherited thrombophilia by measuring serum antithrombin activity, protein C activity, and protein S antigen only in patients that developed VTE. None of them were shown to have inherited thrombophilia by our screening. All of the genetic risk factors for VTE in Japanese were not examined, however, because of the retrospective nature of this study. In fact, we could not precisely assess the existence of protein S K196E [36], which might influence the incidence of VTE in Japanese patients with DLBCL. We conclude that the incidence of VTE in Japanese with DLBCL is comparable to that in the Western population. Patients with poor performance status seemed to have an extremely increased risk for VTE and prophylactic anticoagulants might be beneficial for those patients. Clinicians should provide adequate management of these patients to decrease the risk of VTE. A large-scale prospective study should be conducted to elucidate the subpopulation of patients with lymphoma that would benefit from prophylactic anticoagulants. Conflict of interest statement No conflict of interest. Acknowledgement We would like to thank Dr. Keiko Asakura (Department of Public Health, Keio University School of Medicine) for critical comment on statistical analysis. This work was supported in part by Grant-in-Aid for Blood Coagulation Abnormalities from Ministry Health, Labor, and Welfare of Japan. References [1] Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olson RE. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med 2006;119: 60–8. [2] Kakkar AK, Levine MN, Pinedo HM, Wolff R, Wong J. Venous thrombosis in cancer patients: insights from the frontline survey. Oncologist 2003;8:381–8. [3] Prandoni P, Falanga A, Picoli A. Cancer and venous thromboembolism. Lancet Oncol 2005;6:401–10. [4] Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006;166:458–64. [5] Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007;5:632–4. [6] Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venousthrombosis. JAMA 2005;293:715–22. [7] Khorana AA, Francis CW, Culakova E, Fisher RI, Kuderer NM, Lyman GH. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol 2006;24(3):484–90. [8] Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapyassociated venous thromboembolism in a prospective observational study. Cancer 2005;104(12):2822–9.

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