Semin Thromb Hemost 2012; 38(08): 808-817
DOI: 10.1055/s-0032-1328885
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Thrombotic and Bleeding Complications Associated with Chemotherapy

Brandon J. McMahon
1   Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Chicago, Illinois
,
Hau C. Kwaan
1   Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Chicago, Illinois
› Institutsangaben
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Publikationsverlauf

Publikationsdatum:
10. Oktober 2012 (online)

Abstract

It is well recognized that cancer patients have an increased risk of thrombosis and bleeding. Contributory factors to thrombotic complications include prothrombotic risks carried by many chemotherapeutic agents, type of cancer, stage of cancer, age, and comorbidities. Surgical procedures and the presence of an indwelling vascular device, often used as a mode of delivery for chemotherapy, further increase the risk. Correlative studies have demonstrated upregulation of coagulation in response to chemotherapeutics, and clinical studies have shown that various cancer treatments are independent risk factors for thrombotic complications. It has also been shown that patients who develop thrombosis during treatment have a worse overall prognosis. Mechanisms for chemotherapy and cancer-associated thrombosis are not well understood. Better insight into the mechanism for thrombosis may help better identify those cancer patients at highest risk, who may then benefit from up-front anticoagulant prophylaxis.

 
  • References

  • 1 Trousseau A. Phlegmatia alba dolens. In: Clinique Medicale de l'Hotel-Dieu de Paris. Paris: Balliere; 1865: 654-712
  • 2 White RH, Chew HK, Zhou H , et al. Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults. Arch Intern Med 2005; 165 (15) 1782-1787
  • 3 Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer 2005; 104 (12) 2822-2829
  • 4 Zangari M, Barlogie B, Thertulien R , et al. Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival. Clin Lymphoma 2003; 4 (1) 32-35
  • 5 Escudier SM, Kantarjian HM, Estey EH. Thrombosis in patients with acute promyelocytic leukemia treated with and without all-trans retinoic acid. Leuk Lymphoma 1996; 20 (5–6) 435-439
  • 6 Colović M, Miljić P, Colović N, Janković G, Stojković M. Reversible portal vein thrombosis complicating induction therapy of acute promyelocytic leukemia. Thromb Res 2001; 101 (2) 101-103
  • 7 Goldschmidt N, Gural A, Ben Yehuda D. Extensive splenic infarction, deep vein thrombosis and pulmonary emboli complicating induction therapy with all-trans-retinoic acid (ATRA) for acute promyelocytic leukemia. Leuk Lymphoma 2003; 44 (8) 1433-1437
  • 8 Breccia M, Avvisati G, Latagliata R , et al. Occurrence of thrombotic events in acute promyelocytic leukemia correlates with consistent immunophenotypic and molecular features. Leukemia 2007; 21 (1) 79-83
  • 9 Tallman MS, Abutalib SA, Altman JK. The double hazard of thrombophilia and bleeding in acute promyelocytic leukemia. Semin Thromb Hemost 2007; 33 (4) 330-338
  • 10 Brown JE, Olujohungbe A, Chang J , et al. All-trans retinoic acid (ATRA) and tranexamic acid: a potentially fatal combination in acute promyelocytic leukaemia. Br J Haematol 2000; 110 (4) 1010-1012
  • 11 Hashimoto S, Koike T, Tatewaki W , et al. Fatal thromboembolism in acute promyelocytic leukemia during all-trans retinoic acid therapy combined with antifibrinolytic therapy for prophylaxis of hemorrhage. Leukemia 1994; 8 (7) 1113-1115
  • 12 Wang J, Weiss I, Svoboda K, Kwaan HC. Thrombogenic role of cells undergoing apoptosis. Br J Haematol 2001; 115 (2) 382-391
  • 13 Montesinos P, Sanz MA. The differentiation syndrome in patients with acute promyelocytic leukemia: experience of the pathema group and review of the literature. Mediterr J Hematol Infect Dis 2011; 3 (1) e2011059
  • 14 Rego EM, De Santis GC. Differentiation syndrome in promyelocytic leukemia: clinical presentation, pathogenesis and treatment. Mediterr J Hematol Infect Dis 2011; 3 (1) e2011048
  • 15 De Botton S, Dombret H, Sanz M , et al. Incidence, clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. Blood 1998; 92 (8) 2712-2718
  • 16 Kerbel RS. Tumor angiogenesis. N Engl J Med 2008; 358 (19) 2039-2049
  • 17 Kuenen BC. Analysis of prothrombotic mechanisms and endothelial perturbation during treatment with angiogenesis inhibitors. Pathophysiol Haemost Thromb 2003; 33 (Suppl. 01) 13-14
  • 18 Yang R, Thomas GR, Bunting S , et al. Effects of vascular endothelial growth factor on hemodynamics and cardiac performance. J Cardiovasc Pharmacol 1996; 27 (6) 838-844
  • 19 Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 2008; 300 (19) 2277-2285
  • 20 Hurwitz HI, Saltz LB, Van Cutsem E , et al. Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies. J Clin Oncol 2011; 29 (13) 1757-1764
  • 21 Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA 2011; 305 (5) 487-494
  • 22 Scappaticci FA, Skillings JR, Holden SN , et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 2007; 99 (16) 1232-1239
  • 23 Ranpura V, Hapani S, Chuang J, Wu S. Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials. Acta Oncol 2010; 49 (3) 287-297
  • 24 Hurwitz HI, Fehrenbacher L, Hainsworth JD , et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol 2005; 23 (15) 3502-3508
  • 25 Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 2005; 23 (16) 3706-3712
  • 26 Cooney MM, Tserng KY, Makar V , et al. A phase IB clinical and pharmacokinetic study of the angiogenesis inhibitor SU5416 and paclitaxel in recurrent or metastatic carcinoma of the head and neck. Cancer Chemother Pharmacol 2005; 55 (3) 295-300
  • 27 Kuenen BC, Rosen L, Smit EF , et al. Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. J Clin Oncol 2002; 20 (6) 1657-1667
  • 28 Zangari M, Fink LM, Elice F, Zhan F, Adcock DM, Tricot GJ. Thrombotic events in patients with cancer receiving antiangiogenesis agents. J Clin Oncol 2009; 27 (29) 4865-4873
  • 29 Escudier B, Eisen T, Stadler WM , et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356 (2) 125-134
  • 30 Siu LL, Awada A, Takimoto CH , et al. Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res 2006; 12 (1) 144-151
  • 31 Moore RA, Adel N, Riedel E , et al. High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis. J Clin Oncol 2011; 29 (25) 3466-3473
  • 32 Numico G, Garrone O, Dongiovanni V , et al. Prospective evaluation of major vascular events in patients with nonsmall cell lung carcinoma treated with cisplatin and gemcitabine. Cancer 2005; 103 (5) 994-999
  • 33 Starling N, Rao S, Cunningham D , et al. Thromboembolism in patients with advanced gastroesophageal cancer treated with anthracycline, platinum, and fluoropyrimidine combination chemotherapy: a report from the UK National Cancer Research Institute Upper Gastrointestinal Clinical Studies Group. J Clin Oncol 2009; 27 (23) 3786-3793
  • 34 Czaykowski PM, Moore MJ, Tannock IF. High risk of vascular events in patients with urothelial transitional cell carcinoma treated with cisplatin based chemotherapy. J Urol 1998; 160 (6 Pt 1) 2021-2024
  • 35 Al-Batran SE, Hartmann JT, Probst S , et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 2008; 26 (9) 1435-1442
  • 36 Artero A, Tarín JJ, Cano A. The adverse effects of estrogen and selective estrogen receptor modulators on hemostasis and thrombosis. Semin Thromb Hemost 2012; 38 (8) 797-807
  • 37 Ravandi F, Kantarjian H. Haematological cancer: Gemtuzumab ozogamicin in acute myeloid leukaemia. Nat Rev Clin Oncol 2012; 9 (6) 310-311
  • 38 Castaigne S, Pautas C, Terré C , et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 2012; 379 (9825) 1508-1516
  • 39 Jabbour E, Garcia-Manero G, Cortes J , et al. Twice-daily fludarabine and cytarabine combination with or without gemtuzumab ozogamicin is effective in patients with relapsed/refractory acute myeloid leukemia, high-risk myelodysplastic syndrome, and blast-phase chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk 2012; 12 (4) 244-251
  • 40 Estey E. Treatment of AML: resurrection for gemtuzumab ozogamicin?. Lancet 2012; 379 (9825) 1468-1469
  • 41 Shulman HM, Gown AM, Nugent DJ. Hepatic veno-occlusive disease after bone marrow transplantation. Immunohistochemical identification of the material within occluded central venules. Am J Pathol 1987; 127 (3) 549-558
  • 42 Larson RA, Sievers EL, Stadtmauer EA , et al. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer 2005; 104 (7) 1442-1452
  • 43 McKoy JM, Angelotta C, Bennett CL , et al. Gemtuzumab ozogamicin-associated sinusoidal obstructive syndrome (SOS): an overview from the research on adverse drug events and reports (RADAR) project. Leuk Res 2007; 31 (5) 599-604
  • 44 Jørgensen KA, Sørensen P, Freund L. Effect of glucocorticosteroids on some coagulation tests. Acta Haematol 1982; 68 (1) 39-42
  • 45 Frankfurt O, Rosen ST. Mechanisms of glucocorticoid-induced apoptosis in hematologic malignancies: updates. Curr Opin Oncol 2004; 16 (6) 553-563
  • 46 Mitsiades N, Mitsiades CS, Poulaki V , et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002; 99 (12) 4525-4530
  • 47 Bennett CL, Spiegel DM, Macdougall IC , et al. A review of safety, efficacy, and utilization of erythropoietin, darbepoetin, and peginesatide for patients with cancer or chronic kidney disease: a report from the Southern Network on Adverse Reactions (SONAR) on hemostasis and thrombosis. Semin Thromb Hemost 2012; 38 (8) 783-796
  • 48 Barbui T, Finazzi G, Grassi A, Marchioli R. Thrombosis in cancer patients treated with hematopoietic growth factors—a meta-analysis. On behalf of the Subcommittee on Haemostasis and Malignancy of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1996; 75 (2) 368-371
  • 49 Topcuoglu P, Arat M, Dalva K, Ozcan M. Administration of granulocyte-colony-stimulating factor for allogeneic hematopoietic cell collection may induce the tissue factor-dependent pathway in healthy donors. Bone Marrow Transplant 2004; 33 (2) 171-176
  • 50 LeBlanc R, Roy J, Demers C, Vu L, Cantin G. A prospective study of G-CSF effects on hemostasis in allogeneic blood stem cell donors. Bone Marrow Transplant 1999; 23 (10) 991-996
  • 51 Kuter DJ, Bussel JB, Lyons RM , et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 2008; 371 (9610) 395-403
  • 52 Cheng G, Saleh MN, Marcher C , et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet 2011; 377 (9763) 393-402
  • 53 Grace RF, Dahlberg SE, Neuberg D , et al. The frequency and management of asparaginase-related thrombosis in paediatric and adult patients with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute consortium protocols. Br J Haematol 2011; 152 (4) 452-459
  • 54 Rubinstein LJ, Herman MM, Long TF, Wilbur JR. Disseminated necrotizing leukoencephalopathy: a complication of treated central nervous system leukemia and lymphoma. Cancer 1975; 35 (2) 291-305
  • 55 Lai R, Abrey LE, Rosenblum MK, DeAngelis LM. Treatment-induced leukoencephalopathy in primary CNS lymphoma: a clinical and autopsy study. Neurology 2004; 62 (3) 451-456
  • 56 Mahadeo KM, Dhall G, Panigrahy A, Lastra C, Ettinger LJ. Subacute methotrexate neurotoxicity and cerebral venous sinus thrombosis in a 12-year-old with acute lymphoblastic leukemia and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: homocysteine-mediated methotrexate neurotoxicity via direct endothelial injury. Pediatr Hematol Oncol 2010; 27 (1) 46-52
  • 57 Quinn CT, Kamen BA. A biochemical perspective of methotrexate neurotoxicity with insight on nonfolate rescue modalities. J Investig Med 1996; 44 (9) 522-530
  • 58 Silverstein FS, Johnston MV. A model of methotrexate encephalopathy: neurotransmitter and pathologic abnormalities. J Child Neurol 1986; 1 (4) 351-357
  • 59 Hanson NQ, Aras O, Yang F, Tsai MY. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease. Clin Chem 2001; 47 (4) 661-666
  • 60 Quinn CT, Griener JC, Bottiglieri T, Kamen BA. Methotrexate, homocysteine, and seizures. J Clin Oncol 1998; 16 (1) 393-394
  • 61 Bennett CL, Schumock GT, Desai AA , et al. Thalidomide-associated deep vein thrombosis and pulmonary embolism. Am J Med 2002; 113 (7) 603-606
  • 62 Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. Eastern Cooperative Oncology Group. 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 (3) 431-436
  • 63 Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003; 21 (1) 16-19
  • 64 Barlogie B, Desikan R, Eddlemon P , et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001; 98 (2) 492-494
  • 65 Prince HM, Mileshkin L, Roberts A , et al. A multicenter phase II trial of thalidomide and celecoxib for patients with relapsed and refractory multiple myeloma. Clin Cancer Res 2005; 11 (15) 5504-5514
  • 66 Wu P, Davies FE, Horton C , et al. The combination of cyclophosphomide, thalidomide and dexamethasone is an effective alternative to cyclophosphamide - vincristine - doxorubicin - methylprednisolone as induction chemotherapy prior to autologous transplantation for multiple myeloma: a case-matched analysis. Leuk Lymphoma 2006; 47 (11) 2335-2338
  • 67 Zervas K, Dimopoulos MA, Hatzicharissi E , et al. Primary treatment of multiple myeloma with thalidomide, vincristine, liposomal doxorubicin and dexamethasone (T-VAD doxil): a phase II multicenter study. Ann Oncol 2004; 15 (1) 134-138
  • 68 Facon T, Mary JY, Hulin C , et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet 2007; 370 (9594) 1209-1218
  • 69 Palumbo A, Bringhen S, Caravita T , et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 2006; 367 (9513) 825-831
  • 70 Offidani M, Marconi M, Corvatta L, Olivieri A, Catarini M, Leoni P. Thalidomide plus oral melphalan for advanced multiple myeloma: a phase II study. Haematologica 2003; 88 (12) 1432-1433
  • 71 Rajkumar SV, Hayman S, Gertz MA , et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002; 20 (21) 4319-4323
  • 72 Cavo M, Zamagni E, Cellini C , et al. Deep-vein thrombosis in patients with multiple myeloma receiving first-line thalidomide-dexamethasone therapy. Blood 2002; 100 (6) 2272-2273
  • 73 Barlogie B, Kyle RA, Anderson KC , et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 2006; 24 (6) 929-936
  • 74 Baz R, Li L, Kottke-Marchant K , et al. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc 2005; 80 (12) 1568-1574
  • 75 List A, Kurtin S, Roe DJ , et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005; 352 (6) 549-557
  • 76 Zonder JA, Barlogie B, Durie BG, McCoy J, Crowley J, Hussein MA. Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin prophylaxis. Blood 2006; 108 (1) 403 , author reply 404
  • 77 Rajkumar SV, Jacobus S, Callander NS , et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010; 11 (1) 29-37
  • 78 Zangari M, Fink L, Zhan F, Tricot G. Low venous thromboembolic risk with bortezomib in multiple myeloma and potential protective effect with thalidomide/lenalidomide-based therapy: review of data from phase 3 trials and studies of novel combination regimens. Clin Lymphoma Myeloma Leuk 2011; 11 (2) 228-236
  • 79 Miller SC, Huang R, Sakamuru S , et al. Identification of known drugs that act as inhibitors of NF-kappaB signaling and their mechanism of action. Biochem Pharmacol 2010; 79 (9) 1272-1280
  • 80 Li YD, Ye BQ, Zheng SX , et al. NF-kappaB transcription factor p50 critically regulates tissue factor in deep vein thrombosis. J Biol Chem 2009; 284 (7) 4473-4483
  • 81 Morgan EN, Pohlman TH, Vocelka C , et al. Nuclear factor kappaB mediates a procoagulant response in monocytes during extracorporeal circulation. J Thorac Cardiovasc Surg 2003; 125 (1) 165-171
  • 82 Lonial S, Richardson PG, San Miguel J , et al. Characterisation of haematological profiles and low risk of thromboembolic events with bortezomib in patients with relapsed multiple myeloma. Br J Haematol 2008; 143 (2) 222-229
  • 83 Hiroi T, Deming CB, Zhao H , et al. Proteasome inhibitors enhance endothelial thrombomodulin expression via induction of Krüppel-like transcription factors. Arterioscler Thromb Vasc Biol 2009; 29 (10) 1587-1593
  • 84 Palumbo A, Rajkumar SV, Dimopoulos MA , et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008; 22 (2) 414-423
  • 85 Carrier M, Le Gal G, Tay J, Wu C, Lee AY. Rates of venous thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta-analysis. J Thromb Haemost 2011; 9 (4) 653-663
  • 86 Khorana AA, Connolly GC. Assessing risk of venous thromboembolism in the patient with cancer. J Clin Oncol 2009; 27 (29) 4839-4847
  • 87 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 (1) 60-68
  • 88 Weiss RB, Tormey DC, Holland JF, Weinberg VE. Venous thrombosis during multimodal treatment of primary breast carcinoma. Cancer Treat Rep 1981; 65 (7–8) 677-679
  • 89 Levine MN, Gent M, Hirsh J , et al. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med 1988; 318 (7) 404-407
  • 90 von Tempelhoff GF, Dietrich M, Hommel G, Heilmann L. Blood coagulation during adjuvant epirubicin/cyclophosphamide chemotherapy in patients with primary operable breast cancer. J Clin Oncol 1996; 14 (9) 2560-2568
  • 91 Goodnough LT, Saito H, Manni A, Jones PK, Pearson OH. Increased incidence of thromboembolism in stage IV breast cancer patients treated with a five-drug chemotherapy regimen. A study of 159 patients. Cancer 1984; 54 (7) 1264-1268
  • 92 Rivkin SE, Green S, Metch B , et al. Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study. J Clin Oncol 1994; 12 (10) 2078-2085
  • 93 Amir E, Seruga B, Niraula S, Carlsson L, Ocaña A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst 2011; 103 (17) 1299-1309
  • 94 Scappaticci FA, Skillings JR, Holden SN , et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 2007; 99 (16) 1232-1239
  • 95 Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 2008; 300 (19) 2277-2285
  • 96 Higa GM, Abraham J. Biological mechanisms of bevacizumab-associated adverse events. Expert Rev Anticancer Ther 2009; 9 (7) 999-1007
  • 97 Kirwan CC, McDowell G, McCollum CN, Kumar S, Byrne GJ. Early changes in the haemostatic and procoagulant systems after chemotherapy for breast cancer. Br J Cancer 2008; 99 (7) 1000-1006
  • 98 Mukherjee SD, Swystun LL, Mackman N , et al. Impact of chemotherapy on thrombin generation and on the protein C pathway in breast cancer patients. Pathophysiol Haemost Thromb 2010; 37 (2–4) 88-97
  • 99 Kristinsson SY. Thrombosis in multiple myeloma. Hematology (Am Soc Hematol Educ Program) 2010; 2010: 437-444
  • 100 Kristinsson SY, Björkholm M, Schulman S, Landgren O. Hypercoagulability in multiple myeloma and its precursor state, monoclonal gammopathy of undetermined significance. Semin Hematol 2011; 48 (1) 46-54
  • 101 Zangari M, Berno T, Zhan F, Tricot G, Fink L. Mechanisms of thrombosis in paraproteinemias: the effects of immunomodulatory drugs. Semin Thromb Hemost 2012; 38 (8) 768-779
  • 102 Kristinsson SY, Pfeiffer RM, Bjorkholm M, Schulman S, Landgren O. Thrombosis is associated with inferior survival in multiple myeloma. Haematologica 2012; ; April 17. DOI: 10.3324/haematol.2012.064444. [Epub ahead of print]
  • 103 Maxwell WD, Bennett CL. Thromboprophylaxis guidelines in cancer with a primary focus on ambulatory patients receiving chemotherapy: a review from the Southern Network on Adverse Reactions (SONAR). Semin Thromb Hemost 2012; 38 (8) 759-767
  • 104 Hulin C, Facon T, Rodon P , et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009; 27 (22) 3664-3670
  • 105 Offidani M, Corvatta L, Marconi M , et al. Thalidomide plus oral melphalan compared with thalidomide alone for advanced multiple myeloma. Hematol J 2004; 5 (4) 312-317
  • 106 Richardson PG, Mitsiades C, Hideshima T, Anderson KC. Lenalidomide in multiple myeloma. Expert Rev Anticancer Ther 2006; 6 (8) 1165-1173
  • 107 Dimopoulos M, Spencer A, Attal M , et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007; 357 (21) 2123-2132