Journal of Thrombosis and Haemostasis, 12: 1816–1821

DOI: 10.1111/jth.12724

BRIEF REPORT

Elevated risk of venous but not arterial thrombosis in €m macroglobulinemia/lymphoplasmacytic Waldenstro lymphoma € KHOLM,* L. R. GOLDIN,† I. TURESSON,‡ M . H U L T C R A N T Z , * R . M . P F E I F F E R , † M . B J OR S . S C H U L M A N , * § O . L A N D G R E N ¶ and S . Y . K R I S T I N S S O N * * * † † *Department of Medicine, Division of Hematology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden; †Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; ‡Department of Hematology € , Sweden; §Department of Medicine, McMaster University, Hamilton, ON, and Coagulation disorders, Sk ane University Hospital, Malmo Canada; ¶Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; **Faculty of Medicine, University of Iceland; and ††Department of Hematology, Landspitali National University Hospital, Reykjavik, Iceland

€ rkholm M, Goldin LR, Turesson I, Schulman S, Landgren O, Kristinsson SY. Elevated risk To cite this article: Hultcrantz M, Pfeiffer RM, Bjo € m macroglobulinemia/lymphoplasmacytic lymphoma. J Thromb Haemost 2014; of venous but not arterial thrombosis in Waldenstro 12: 1816–21.

Summary. Background: Many malignancies, including multiple myeloma and its precursor, monoclonal gammopathy of unknown significant, are associated with an elevated risk of thromboembolism. There is limited information on the risk of thrombosis in patients with Waldenstr€ om macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL). Objectives: To assess the risk of venous and arterial thrombosis in WM/LPL patients in a large population-based cohort study in Sweden. Patients/methods: A total of 2190 patients with WM/LPL and 8086 matched controls were identified through Swedish registers between 1987 and 2005. Information on occurrence of venous and arterial thrombosis after the diagnosis of WM/LPL was obtained through the centralized Swedish Patient Register, with follow-up to 2006. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Patients with WM/LPL had a significantly increased risk of venous thrombosis and the highest risk was observed during the first year following diagnosis (HR = 4.0, 95% CI 2.5–6.4). The risk was significantly elevated 5 (HR = 2.3, 95% CI 1.7–3.0) and 10 years after diagnosis (HR = 2.0, 95% CI 1.6–2.5). There was no increased risk of arterial thrombosis during any period of follow-up Correspondence: Malin Hultcrantz, Division of Hematology, Department of Medicine, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden. Tel.: +46 8 51770000; fax: +46 8 318264. E-mail: [email protected] Received 10 April 2014 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 1 September 2014

time (10-year HR = 1.0, 95% CI 0.9–1.1). Conclusions: Venous thrombosis is a significant cause of morbidity in patients with WM/LPL. The potential role of thromboprophylaxis in WM/LPL, especially during the first year after diagnosis and in patients treated with thrombogenic agents, needs to be assessed to further improve outcome in WM/LPL patients. Keywords: embolism and thrombosis; lymphoma, B cell; thrombosis; venous thrombosis; Waldenstr€ om macroglobulinemia.

Introduction Waldenstr€ om macroglobulinemia (WM) is a disease characterized by lymphoplasmacytic lymphoma (LPL) in the bone marrow and IgM paraproteinemia of any size [1]. The disease is classified as LPL in the absence of IgM paraprotein. Recently, the MYD88 L265P somatic mutation was discovered, which is present in > 90% of WM/ LPL patients and in > 50% of IgM monoclonal gammopathy of unknown significance (MGUS0 patients [2–4]. Patients with WM may have an increased risk of bleeding due to the IgM paraproteinemia-associated hyperviscosity. However, the literature on thromboembolic events in WM/LPL is limited to a few case reports [5,6]. Thrombosis is a significant cause of morbidity and mortality in cancer patients, and it is well documented that patients with lymphoma and multiple myeloma (MM) have an increased risk of venous and arterial thrombosis [7]. The risk is especially high in MM patients treated with immunomodulatory drugs (IMiDs) and thromboprophylaxis is recommended when starting therapy with these drugs © 2014 International Society on Thrombosis and Haemostasis

Thrombosis in WM/LPL 1817

[8–11]. In a population-based study in Sweden, patients with IgG and IgA MGUS had a higher risk of both venous and arterial thrombosis compared to the general population, while there was no increase in risk in patients with IgM MGUS [12]. We conducted a large population-based study of > 2000 patients with WM/LPL and > 8000 matched controls in Sweden, to assess the risk of venous and arterial thrombosis in WM/LPL patients. Patients/methods Central registers

Sweden provides universal medical health care for the entire population, currently ~ 9.5 million people. Diagnoses of malignant diseases (including WM/LPL) in Sweden are reported to the population-based nationwide Swedish Cancer Register, which was established in 1958 [13]. The centralized Swedish Patient Register captures information on individual patient-based discharge diagnoses from inpatient records since 1964 and from outpatient records since 2001 [14]. In Sweden, each individual receives a unique national registration number and every death date is recorded in the Cause of Death Register. All patients with a reported diagnosis of WM or LPL in the Swedish Cancer Register between January 1, 1987, and December 31, 2005, were identified and included in the cohort, as described earlier [15]. Due to underreporting of WM/LPL to the register [16], additional cases were identified through the Swedish Patient Register and through a national network including all hematology and oncology centers in Sweden. For each patient, four controls matched for age, gender, and county of residence were identified through the Swedish Register of Total Population. Information on occurrence of venous and arterial thrombosis after the diagnosis of WM/LPL (selection for controls) was obtained through the Swedish Patient Register [14]. Venous thrombosis was defined as pulmonary embolism or deep vein thrombosis and arterial thrombosis was defined as myocardial infarction, angina pectoris, cerebral infarction, or transient ischemic attack. Sensitivity analyses of deep venous thrombosis only and myocardial infarction and stroke only were performed. Also, WM and LPL patients were analyzed separately, and as there was no difference in the risk estimates and the fact that > 95% of LPL patients have been shown to have IgM paraprotein and, thus, WM [17], the results are presented for WM/LPL patients combined. Cox regression models (SAS 9.2 PROC PHREG, SAS Institute Inc., Cary, NC, USA) adjusted for sex, age at diagnosis (selection), and year of diagnosis (selection) were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Incidence rates (IRs) were calculated for both venous and arterial thrombosis. Time since diagnosis (selection) was used as the time metric. Patients © 2014 International Society on Thrombosis and Haemostasis

and controls were followed from diagnosis (selection) until time of thrombosis, death, or end of follow-up (December 31, 2006). Analyses of HRs at 1, 5, and 10 years after diagnosis/selection were performed. In a sensitivity analysis of risk of thrombosis during followup, the 5-year HR was calculated excluding all events that occurred during the first year after diagnosis/selection. Analyses that used age as the time metric gave similar results (data not shown). Kaplan–Meier survival curves for WM/LPL patients and matched controls were plotted using MATLABR 2012b (The MathWorks, Inc., Natick, MA, USA). The study was approved by the Stockholm Regional Ethics Review Board. Informed consent was waived, because we had no contact with study patients and the data used for analyses did not contain any personal identifiers. Results and discussion A total of 1606 patients with WM, 584 patients with LPL, and 8086 matched controls were identified between 1987 and 2005. The median age at diagnosis of WM/LPL was 74 years (range 18–100 years), and 58% were men. Patients with WM/LPL had a significantly elevated risk of venous thrombosis compared with matched controls, with the highest risk observed during the first year after diagnosis (HR = 4.0, 95% CI 2.5–6.4, P < 0.001). There was a significant increase in the risk of venous thrombosis 5 and 10 years after diagnosis, reflected by HRs of 2.3 (1.7–3.0, P < 0.001) and 2.0 (1.6–2.5, P < 0.001), respectively (Table 1; Fig. 1). In a sensitivity analysis where all events occurring during the first year after diagnosis were excluded, the 5-year HRs was still significantly increased (HR = 1.8, 1.2–2.6, P = 0.002). There was no difference in the HRs of venous or arterial thrombosis when WM and LPL were analyzed separately. Also, analysis restricted to deep vein thrombosis showed similar results to the analysis of all venous thrombosis combined (data not shown). The increase in risk of venous and arterial thrombosis was similar for both genders compared with controls (Table 1). Our finding of an increased risk of venous thrombosis in WM/LPL is of clinical interest. An elevated risk of venous thrombosis has been described in patients with lymphomas and MM [12,18]; however, there are, to our knowledge, no large studies of the risk of thrombosis in patients with WM/LPL. Only a few case reports have so far been published on central retinal vein thrombosis in patients with WM [5,6]. The reason for the elevated risk of venous thrombosis is most likely multifactorial. The hyperviscosity associated with a high IgM paraprotein in WM/LPL has been correlated with impaired blood flow, especially regarding the microvascular circulation [19–21]. The IgM paraprotein may also interact with red blood cells, platelets, coagulation factors, and adhesive molecules and thereby promote formation of thrombi [21].

Venous thrombosis

1 0.95

Event-free survival

WM, Waldenstr€ om macroglobulinemia; LPL, Lymphoplasmacytic lymphoma; IR, Incidence rate; HR, Hazard ratio; pts, patients; ctrls, controls. *Models were adjusted for age and year at diagnosis/selection and gender. †Venous thrombosis = Deep venous thrombosis or pulmonary embolism. ‡Arterial thrombosis = Myocardial infarction, angina pectoris, cerebral infarction, or transient ischemic attack. §Coronary artery disease = Myocardial infarction, angina pectoris. ¶Cerebrovascular disease = Cerebral infarction, transient ischemic attack.

(1.6–2.5) (1.3–2.5) (1.5–3.2) (0.9–1.1) (0.7–1.0) (0.9–1.3) (0.9–1.1) (0.8–1.1) 2.0 1.8 2.2 1.0 0.9 1.1 1.0 0.9 1.4 1.5 1.3 10.3 11.0 9.3 6.5 4.5 255 157 98 1781 1144 734 1245 911 34 18 16 101 60 42 72 37 Venous thrombosis† Males Females Arterial thrombosis‡ Males Females Coronary artery disease§ Cerebrovascular disease¶

34 20 14 334 222 100 230 119

2.0 1.9 2.0 12.4 13.9 10.4 8.5 4.4

4.0 (2.5–6.4) 3.7 (2.0–7.0) 4.4 (2.1–9.1) 1.2 (0.99–1.5) 1.1 (0.8–1.4) 1.6 (1.1–2.2) 1.2 (0.95–1.6) 1.3 (0.9–1.9)

73 39 34 256 152 115 181 107

(1.7–3.0) (1.4–2.9) (1.8–4.3) (0.9–1.2) (0.8–1.1) (0.9–1.4) (0.9–1.2) (0.8–1.2) 2.3 2.0 2.8 1.0 0.9 1.1 1.1 1.0 1.5 1.6 1.4 10.4 11.2 9.3 6.7 4.3 155 98 57 1195 736 448 812 556

92 51 41 329 190 152 229 152

Ctrls WM/LPL pts HR* (95% CI) IR Ctrls WM/LPL pts WM/LPL pts Thrombosis by location and by gender

Ctrls

IR

HR* (95% CI)

5-year follow-up 1-year follow-up

Table 1 Number of events and risk estimates for venous and arterial thrombosis among WM/LPL patients (vs. matched controls)

10-year follow-up

IR

HR* (95% CI)

1818 M. Hultcrantz et al

0.9 0.85 0.8 0.75 0.7 0.65

WM/LPL patients Controls

0

WM/LPL patients:

2

4 6 8 Time since diagonsis (years)

10

756

476

318

249

394

Controls: 1308

1593

1328

1122

2735

Fig. 1. Event-free survival from venous thrombosis in patients with Waldenstr€ om macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL) compared to matched controls. Number of WM/ LPL patients and controls at risk are shown below the figure.

Tumor cells may express procoagulant factors and interact with endothelial and blood cells [12]. In addition, tumor-induced inflammation and elevated levels of factor VIII and other procoagulant factors have been reported in patients with WM. [22,23] Many hematological malignancies are associated with a hypercoagulable state where several additional mechanisms may be included. Hostrelated mechanisms include age, previous thrombosis, underlying co-morbidities, immobilization, and inherited thrombophilia. Moreover, treatment with chemotherapy (especially anthracyclines), corticosteroids, and erythropoietin as well as infections may contribute to the elevated risk of venous thrombosis [7,10,24–26]. Significant lymphadenopathy and the use of in-dwelling venous catheters are rare in WM/LPL patients; therefore, venous stasis and catheters are less common reasons for thrombosis in these patients [18]. Although several underlying mechanisms of venous thrombosis in patients with hematological malignancies have been suggested, the role of hyperviscosity in venous thrombosis needs to be elucidated to better understand the thrombotic mechanisms in patients with WM/LPL. The risk of thrombosis was highest during the first year following diagnosis, a similar pattern as has been observed in MM patients [12]. A large tumor burden and hyperviscosity at diagnosis as well as the treatmentrelated factors mentioned earlier may contribute to the prothrombotic state seen during the first year after diagnosis. In a prospective trial on lymphoma and thromboembolism, the highest risk was confined to patients on chemotherapy, particularly during the first 3 months of © 2014 International Society on Thrombosis and Haemostasis

Thrombosis in WM/LPL 1819

treatment [18]. Although the risk was highest during the first year after diagnosis in our study, the risk of venous thrombosis was elevated 5 and 10 years after diagnosis. Whether this continuous increase in risk of venous thrombosis is related to patient-, treatment-, or tumor-associated factors during follow-up needs to be clarified. We found no increase in the risk of arterial thrombosis during any period of follow-up in patients with WM/ LPL, reflected by HRs of 1.2 (0.99–1.5), 1.0 (0.9–1.2), and 1.0 (0.9–1.1) after 1, 5, and 10 years, respectively (Table 1). A sensitivity analysis restricted to myocardial infarction and stroke, thus excluding angina pectoris and transient ischemic attacks, resulted in similar outcomes (data not shown). Risks were also similar when coronary and cerebral arterial thrombosis were analyzed separately; 10-year HRs were 1.0 (0.9–1.1) and 0.9 (0.8–1.1), respectively (Table 1, Fig. 2). This is, to our knowledge, the first study to evaluate the risk of arterial thrombosis in WM/LPL and interestingly, the results differ from previous findings in other paraprotein disorders such as MM and IgG and IgA MGUS, where an increased risk of arterial thrombosis has been observed [12]. However, the results are consistent with our previous findings that patients with IgM MGUS do not have an increased risk of arterial thrombosis [12]. In fact, it has been suggested that the IgM paraprotein can impair platelet aggregation and thereby may prevent arterial thromboembolism [21]. The use of IMiDs and the associated thromboprophylaxis with aspirin or other anticoagulants in patients with WM/LPL was limited during the study period [27]. Also,

Arterial thrombosis 1

Event-free survival

0.95 0.9 0.85 0.8 0.75 0.7 0.65

WM/LPL patients Controls

0

2

4 6 8 Time since diagnosis (years)

10

Addendum

WM/LPL patients:

701

464

321

264

440

Controls:

927

1459

1290

1168

3242

Fig. 2. Event-free survival from arterial thrombosis in patients with Waldenstr€ om macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL) compared to matched controls. Number of WM/ LPL patients and controls at risk are shown below the figure. © 2014 International Society on Thrombosis and Haemostasis

the first reports on elevated risks of thrombosis during IMiD treatment were published after the study period [11]. Therefore, we have no reason to assume a more frequent use of aspirin or anticoagulants in WM/LPL patients. In females, there was a moderate increase in arterial thrombosis during the first year after diagnosis (HR = 1.6; 1.1–2.2, P = 0.01); however, there was no significant increase in the risk after 5 and 10 years of follow-up. The reason for the elevated risk in females during the first year after diagnosis is largely unknown, but gender differences in disease biology, response to treatment, and also surveillance bias may be of importance. Our presented findings of elevated risk of venous thrombosis indicate that certain WM/LPL patients may benefit from thromboprophylaxis. We recommend clinicians to follow the general guidelines for prevention of cancer-associated venous thrombosis [28,29]. In MM, treatment with IMiDs (thalidomide and lenalidomide) is associated with a high risk of venous thrombosis during initial treatment [8,9], and prophylactic measures are recommended based on risk factors [10,11]. Extrapolating from the guidelines for MM and cancer-associated venous thrombosis [10,28], prophylaxis with anticoagulation should be considered in patients with WM/LPL treated with IMiDs. Further studies are needed to elucidate which additional WM/LPL patients would benefit from thromboprophylaxis. Our study has several strengths, including the large number of patients, long follow-up times, and the population-based setting with information based on high-quality registers. The diagnostic accuracy of the Swedish Patients Register has been validated and is very high, in particular arterial thrombosis was > 95% [14]. A limitation is the lack of detailed clinical information including comorbidities, risk factors, management, and individual levels of IgM paraprotein both in patients with WM and LPL. In summary, in this large population-based study, patients with WM/LPL had a significantly 2- to 4-fold elevated risk of venous thrombosis but not of arterial thrombosis compared to matched controls. Venous thrombosis is the second leading cause of death in cancer patients, and it is of great importance to assess the individual risk of thrombosis in each patient [26,30]. Future studies are needed to assess the thrombotic mechanisms in WM and the role of thromboprophylaxis in WM/LPL, especially in the first year after diagnosis and during treatment with thrombogenic treatments.

M. Hultcrantz, S. Y. Kristinsson, M. Bj€ orkholm, I. Turesson, and O. Landgren designed the study, obtained data, and initiated this work; R. M. Pfeiffer performed all statistical analyses; M. Hultcrantz, S. Y. Kristinsson, and R. M. Pfeiffer wrote the report; all the authors were involved in the interpretation of the results; read, gave

1820 M. Hultcrantz et al

comments, and approved the final version of the manuscript; had full access to the data in the study; and take responsibility for the accuracy of the data analysis. Acknowledgements The authors would like to thank David Check for help with the graphical presentation of the figures. We would also like to thank Blodcancerfonden, the Swedish Cancer Society, the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Karolinska Institutet Foundations, the University of Iceland Research Fund, Icelandic Centre for Research (RANNIS), and Landspitali University Hospital Research Fund. Disclosure of Conflict of Interests The authors state that they have no conflict of interests. References 1 Gertz MA. Waldenstrom macroglobulinemia: 2013 update on diagnosis, risk stratification, and management. Am J Hematol 2013; 88: 703–11. 2 Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Sheehy P, Manning RJ, Patterson CJ, Tripsas C, Arcaini L, Pinkus GS, Rodig SJ, Sohani AR, Harris NL, Laramie JM, Skifter DA, Lincoln SE, Hunter ZR. MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia. N Engl J Med 2012; 367: 826–33. 3 Xu L, Hunter ZR, Yang G, Zhou Y, Cao Y, Liu X, Morra E, Trojani A, Greco A, Arcaini L, Varettoni M, Brown JR, Tai YT, Anderson KC, Munshi NC, Patterson CJ, Manning RJ, Tripsas CK, Lindeman NI, Treon SP. MYD88 L265P in Waldenstrom macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. Blood 2013; 121: 2051–8. 4 Landgren O, Staudt L. MYD88 L265P somatic mutation in IgM MGUS. N Engl J Med 2012; 367: 2255–6; author reply 6–7. 5 Chanana B, Gupta N, Azad RV. Case report: bilateral simultaneous central retinal vein occlusion in Waldenstrom’s macroglobulinemia. Optometry 2009; 80: 350–3. 6 Alexander P, Flanagan D, Rege K, Foss A, Hingorani M. Bilateral simultaneous central retinal vein occlusion secondary to hyperviscosity in Waldenstrom’s macroglobulinaemia. Eye (Lond) 2008; 22: 1089–92. 7 Kristinsson SY, Bjorkholm M, Schulman S, Landgren O. Hypercoagulability in multiple myeloma and its precursor state, monoclonal gammopathy of undetermined significance. Semin Hematol 2011; 48: 46–54. 8 Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006; 24: 431–6. 9 Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foa R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007; 357: 2123–32.

10 Kristinsson SY. Thrombosis in multiple myeloma. Hematology Am Soc Hematol Educ Program 2010; 2010: 437–44. 11 Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B, Harousseau J, Zonder JA, Cavo M, Zangari M, Attal M, Belch A, Knop S, Joshua D, Sezer O, Ludwig H, Vesole D, Blade J, Kyle R, Westin J, et al. International Myeloma Working Group. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008; 22: 414–23. 12 Kristinsson SY, Pfeiffer RM, Bjorkholm M, Goldin LR, Schulman S, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study. Blood 2010; 115: 4991–8. 13 Cancer Incidence in Sweden 2010. Official Statistics of Sweden. Stockholm: National Board of Health and Welfare, Centre for Epidemiology, 2011. 14 Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C, Heurgren M, Olausson PO. External review and validation of the Swedish national inpatient register. BMC Public Health 2011; 11: 450. 15 Kristinsson SY, Eloranta S, Dickman PW, Andersson TM, Turesson I, Landgren O, Bjorkholm M. Patterns of survival in lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia: a population-based study of 1,555 patients diagnosed in Sweden from 1980 to 2005. Am J Hematol 2013; 88: 60–5. 16 Turesson I, Linet MS, Bjorkholm M, Kristinsson SY, Goldin LR, Caporaso NE, Landgren O. Ascertainment and diagnostic accuracy for hematopoietic lymphoproliferative malignancies in Sweden 1964-2003. Int J Cancer 2007; 121: 2260–6. 17 Treon SP. How I treat Waldenstrom macroglobulinemia. Blood 2009; 114: 2375–85. 18 Park LC, Woo SY, Kim S, Jeon H, Ko YH, Kim SJ, Kim WS. Incidence, risk factors and clinical features of venous thromboembolism in newly diagnosed lymphoma patients: results from a prospective cohort study with Asian population. Thromb Res 2012; 130: e6–12. 19 Stone MJ, Bogen SA. Evidence-based focused review of management of hyperviscosity syndrome. Blood 2012; 119: 2205–8. 20 Reinhart WH, Lutolf O, Nydegger UR, Mahler F, Straub PW. Plasmapheresis for hyperviscosity syndrome in macroglobulinemia Waldenstrom and multiple myeloma: influence on blood rheology and the microcirculation. J Lab Clin Med 1992; 119: 69– 76. 21 Kwaan HC. Hyperviscosity in plasma cell dyscrasias. Clin Hemorheol Microcirc 2013; 55: 75–83. 22 Zangari M, Elice F, Fink L, Tricot G. Hemostatic dysfunction in paraproteinemias and amyloidosis. Semin Thromb Hemost 2007; 33: 339–49. 23 Auwerda JJ, Sonneveld P, de Maat MP, Leebeek FW. Prothrombotic coagulation abnormalities in patients with paraprotein-producing B-cell disorders. Clin Lymphoma Myeloma 2007; 7: 462–6. 24 Falanga A, Marchetti M, Russo L. Venous thromboembolism in the hematologic malignancies. Curr Opin Oncol 2012; 24: 702– 10. 25 Hedenus M, Osterborg A, Tomita D, Bohac C, Coiffier B. Effects of erythropoiesis-stimulating agents on survival and other outcomes in patients with lymphoproliferative malignancies: a study-level meta-analysis. Leuk Lymphoma 2012; 53: 2151–8. 26 Falanga A, Marchetti M. Anticancer treatment and thrombosis. Thromb Res 2012; 129: 353–9. 27 Ghobrial IM, Gertz MA, Fonseca R. Waldenstrom macroglobulinaemia. Lancet Oncol 2003; 4: 679–85. 28 Streiff MB, Bockenstedt PL, Cataland SR, Chesney C, Eby C, Fanikos J, Fogerty AE, Gao S, Goldhaber SZ, Hassoun H, Hendrie P, Holmstrom B, Kuderer N, Lee JT, Millenson MM, © 2014 International Society on Thrombosis and Haemostasis

Thrombosis in WM/LPL 1821 Neff AT, Ortel TL, Siddiqi T, Smith JL, Yee GC, et al. National comprehensive cancer n. Venous thromboembolic disease. J Natl Compr Canc Netw 2013; 11: 1402–29. 29 Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, Cook DJ, Balekian AA, Klein RC, Le H, Schulman S, Murad MH, American College of Chest Physicians. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention

© 2014 International Society on Thrombosis and Haemostasis

of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e195S–226S. 30 Kristinsson SY, Pfeiffer RM, Bjorkholm M, Schulman S, Landgren O. Thrombosis is associated with inferior survival in multiple myeloma. Haematologica 2012; 97: 1603–7.

lymphoplasmacytic lymphoma.

Many malignancies, including multiple myeloma and its precursor, monoclonal gammopathy of unknown significant, are associated with an elevated risk of...
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