Download PDF
Semin Thromb Hemost 2011; 37(8): 929-945
DOI: 10.1055/s-0031-1297372
© Thieme Medical Publishers

Bleeding and Thrombosis in Multiple Myeloma and Related Plasma Cell Disorders

Antonio Coppola1 , Antonella Tufano1 , Mirko Di Capua1 , Massimo Franchini2
  • 1Regional Reference Center for Coagulation Disorders, Federico II University Hospital, Naples, Italy
  • 2Immunohematology and Transfusion Center, Department of Pathology and Laboratory Medicine, University Hospital, Parma, Italy
Further Information

Publication History

Publication Date:
23 December 2011 (online)

    Permissions and Reprints

ABSTRACT

A variety of disease- and treatment-related factors affect the coagulation system and the risk of bleeding and thrombotic complications in patients with multiple myeloma (MM) and related plasma cell disorders (PCD). As commonly observed in other cancer settings, the malignant clone induces a cytokine environment responsible for a hypercoagulable state. The increase of blood viscosity and impairment of platelet and coagulation function due to circulating monoclonal proteins are considered key mechanisms in the hemostatic abnormalities frequently detected in patients with PCD. However, clinically significant bleeding is relatively rare and poorly correlated with these abnormalities. Management is often challenging because of the multifactorial pathogenesis and underestimation or misdiagnosis of acquired bleeding disorders, particularly acquired von Willebrand syndrome. In recent years, growing interest in thromboembolic risk has emerged after the introduction of novel and more effective antimyeloma agents (thalidomide and lenalidomide), which was associated with increased risk of venous thromboembolism, particularly when associated with dexamethasone and multiagent chemotherapy in newly diagnosed patients. The clinical impact of bleeding and thrombotic complications in patients with PCD, with emphasis on MM, will be discussed in this review, reporting the current knowledge about pathophysiologic mechanisms and implications for management.

KEYWORDS

Bleeding - hypercoagulability - M protein - multiple myeloma - plasma cell disorders - prophylaxis - thrombosis

REFERENCES

  • 1 Green D. Management of bleeding complications of hematologic malignancies.  Semin Thromb Hemost. 2007;  33 (4) 427-434
    Google Scholar
  • 2 Chong B H, Lee S-H. Management of thromboembolism in hematologic malignancies.  Semin Thromb Hemost. 2007;  33 (4) 435-448
    Google Scholar
  • 3 Franchini M, Dario Di Minno M N, Coppola A. Disseminated intravascular coagulation in hematologic malignancies.  Semin Thromb Hemost. 2010;  36 (4) 388-403
    Google Scholar
  • 4 Falanga A, Ofosu F A, Delaini F et al.. The hypercoagulable state in cancer patients: evidence for impaired thrombin inhibitions.  Blood Coagul Fibrinolysis. 1994;  5 (Suppl 1) S19-S23, discussion 59–64
    Google Scholar
  • 5 Falanga A, Rickles F R. Pathophysiology of the thrombophilic state in the cancer patient.  Semin Thromb Hemost. 1999;  25 (2) 173-182
    Google Scholar
  • 6 Zangari M, Elice F, Fink L, Tricot G. Hemostatic dysfunction in paraproteinemias and amyloidosis.  Semin Thromb Hemost. 2007;  33 (4) 339-349
    Google Scholar
  • 7 Eby C. Pathogenesis and management of bleeding and thrombosis in plasma cell dyscrasias.  Br J Haematol. 2009;  145 (2) 151-163
    Google Scholar
  • 8 Zangari M, Anaissie E, Barlogie B et al.. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy.  Blood. 2001;  98 (5) 1614-1615
    Google Scholar
  • 9 Kyle R A, Gertz M A, Witzig T E et al.. Review of 1027 patients with newly diagnosed multiple myeloma.  Mayo Clin Proc. 2003;  78 (1) 21-33
    Google Scholar
  • 10 Kumar S K, Rajkumar S V, Dispenzieri A et al.. Improved survival in multiple myeloma and the impact of novel therapies.  Blood. 2008;  111 (5) 2516-2520
    Google Scholar
  • 11 Uaprasert N, Voorhees P M, Mackman N, Key N S. Venous thromboembolism in multiple myeloma: current perspectives in pathogenesis.  Eur J Cancer. 2010;  46 (10) 1790-1799
    Google Scholar
  • 12 Zamagni E, Brioli A, Tacchetti P, Zannetti B, Pantani L, Cavo M. Multiple myeloma, venous thromboembolism, and treatment-related risk of thrombosis.  Semin Thromb Hemost. 2011;  37 (3) 209-219
    Google Scholar
  • 13 Rajkumar S V, Dispenzieri A, Kyle R A. Monoclonal gammopathy of undetermined significance, Waldenström macroglobulinemia, AL amyloidosis, and related plasma cell disorders: diagnosis and treatment.  Mayo Clin Proc. 2006;  81 (5) 693-703
    Google Scholar
  • 14 Kristinsson S Y, Fears T R, Gridley G et al.. Deep vein thrombosis after monoclonal gammopathy of undetermined significance and multiple myeloma.  Blood. 2008;  112 (9) 3582-3586
    Google Scholar
  • 15 Kyle R A, Rajkumar S V. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma.  Leukemia. 2009;  23 (1) 3-9
    Google Scholar
  • 16 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun M J. Cancer statistics, 2009.  CA Cancer J Clin. 2009;  59 (4) 225-249
    Google Scholar
  • 17 Perkins H A, MacKenzie M R, Fudenberg H H. Hemostatic defects in dysproteinemias.  Blood. 1970;  35 (5) 695-707
    Google Scholar
  • 18 Niléhn J E, Nilsson I M. Coagulation studies in different types of myeloma.  Acta Med Scand Suppl. 1966;  445 194-199
    Google Scholar
  • 19 Penny R, Castaldi P A, Whitsed H M. Inflammation and haemostasis in paraproteinaemias.  Br J Haematol. 1971;  20 (1) 35-44
    Google Scholar
  • 20 Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias.  Semin Thromb Hemost. 2003;  29 (5) 467-471
    Google Scholar
  • 21 Kwaan H C, Bongu A. The hyperviscosity syndromes.  Semin Thromb Hemost. 1999;  25 (2) 199-208
    Google Scholar
  • 22 Crawford J, Cox E B, Cohen H J. Evaluation of hyperviscosity in monoclonal gammopathies.  Am J Med. 1985;  79 (1) 13-22
    Google Scholar
  • 23 Sucker C, Hetzel G R, Grabensee B, Stockschlaeder M, Scharf R E. Amyloidosis and bleeding: pathophysiology, diagnosis, and therapy.  Am J Kidney Dis. 2006;  47 (6) 947-955
    Google Scholar
  • 24 Kyle R A. Multiple myeloma: review of 869 cases.  Mayo Clin Proc. 1975;  50 (1) 29-40
    Google Scholar
  • 25 Rossi D, De Paoli L, Franceschetti S et al.. Prevalence and clinical characteristics of immune thrombocytopenic purpura in a cohort of monoclonal gammopathy of uncertain significance.  Br J Haematol. 2007;  138 (2) 249-252
    Google Scholar
  • 26 Alpay N, Uzun S, Bahat G, Yavuz S, Erten N, Tascioglu C. Thrombotic thrombocytopenic purpura associated with multiple myeloma.  Blood Coagul Fibrinolysis. 2008;  19 (5) 439-441
    Google Scholar
  • 27 Hofmeister C C, Jin M, Cataland S R, Benson D M, Wu H M. TTP disease course is independent of myeloma treatment and response.  Am J Hematol. 2010;  85 (4) 304-306
    Google Scholar
  • 28 Sharma P, Kar R, Bhargava R, Ranjan R, Mishra PC, Saxena R. Acquired platelet dysfunction in 109 patients from a tertiary care referral hospital.  Clin Appl Thromb Hemost. 2011;  17 (1) 88-93
    Google Scholar
  • 29 DiMinno G, Coraggio F, Cerbone A M et al.. A myeloma paraprotein with specificity for platelet glycoprotein IIIa in a patient with a fatal bleeding disorder.  J Clin Invest. 1986;  77 (1) 157-164
    Google Scholar
  • 30 Ingram G I, Kingston P J, Leslie J, Bowie E J. Four cases of acquired von Willebrand's syndrome.  Br J Haematol. 1971;  21 (2) 189-199
    Google Scholar
  • 31 Handin R I, Martin V, Moloney W C. Antibody-induced von Willebrand's disease: a newly defined inhibitor syndrome.  Blood. 1976;  48 (3) 393-405
    Google Scholar
  • 32 Federici A B, Budde U, Rand J H. Acquired von Willebrand syndrome 2004: International Registry—diagnosis and management from online to bedside.  Hamostaseologie. 2004;  24 (1) 50-55
    Google Scholar
  • 33 Franchini M, Lippi G. Acquired von Willebrand syndrome: an update.  Am J Hematol. 2007;  82 (5) 368-375
    Google Scholar
  • 34 Tiede A, Priesack J, Werwitzke S et al.. Diagnostic workup of patients with acquired von Willebrand syndrome: a retrospective single-centre cohort study.  J Thromb Haemost. 2008;  6 (4) 569-576
    Google Scholar
  • 35 Federici A B. Acquired von Willebrand syndrome: an underdiagnosed and misdiagnosed bleeding complication in patients with lymphoproliferative and myeloproliferative disorders.  Semin Hematol. 2006;  43 (1, Suppl 1) S48-S58
    Google Scholar
  • 36 Federici A B. Acquired von Willebrand syndrome: is it an extremely rare disorder or do we see only the tip of the iceberg?.  J Thromb Haemost. 2008;  6 (4) 565-568
    Google Scholar
  • 37 International Registry on Acquired von Willebrand Syndrome .Available at http://www.intreavws.com Accessed on January 21, 2011
  • 38 Michiels J J, Budde U, van der Planken M, van Vliet H H, Schroyens W, Berneman Z. Acquired von Willebrand syndromes: clinical features, aetiology, pathophysiology, classification and management.  Best Pract Res Clin Haematol. 2001;  14 (2) 401-436
    Google Scholar
  • 39 Scrobohaci M L, Daniel M T, Levy Y, Marolleau J P, Brouet J C. Expression of GpIb on plasma cells in a patient with monoclonal IgG and acquired von Willebrand disease.  Br J Haematol. 1993;  84 (3) 471-475
    Google Scholar
  • 40 Eikenboom J C, van der Meer F J, Briët E. Acquired von Willebrand's disease due to excessive fibrinolysis.  Br J Haematol. 1992;  81 (4) 618-620
    Google Scholar
  • 41 Shinagawa A, Kojima H, Berndt M C et al.. Characterization of a myeloma patient with a life-threatening hemorrhagic diathesis: presence of a lambda dimer protein inhibiting shear-induced platelet aggregation by binding to the A1 domain of von Willebrand factor.  Thromb Haemost. 2005;  93 (5) 889-896
    Google Scholar
  • 42 van Genderen P J, Vink T, Michiels J J, van 't Veer M B, Sixma J J, van Vliet H H. Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen.  Blood. 1994;  84 (10) 3378-3384
    Google Scholar
  • 43 Siaka C, Rugeri L, Caron C, Goudemand J. A new ELISA assay for diagnosis of acquired von Willebrand syndrome.  Haemophilia. 2003;  9 (3) 303-308
    Google Scholar
  • 44 Coleman R, Favaloro E J, Soltani S, Keng T B. Acquired von Willebrand disease: potential contribution of the VWF:CB to the identification of functionally inhibiting auto-antibodies to von Willebrand factor.  J Thromb Haemost. 2006;  4 (9) 2085-2088
    Google Scholar
  • 45 Guerin V, Ryman A, Velez F. Acquired von Willebrand disease: potential contribution of the von Willebrand factor collagen-binding to the identification of functionally inhibiting auto-antibodies to von Willebrand factor: a rebuttal.  J Thromb Haemost. 2008;  6 (6) 1051-1052
    Google Scholar
  • 46 Mohri H, Motomura S, Kanamori H et al.. Clinical significance of inhibitors in acquired von Willebrand syndrome.  Blood. 1998;  91 (10) 3623-3629
    Google Scholar
  • 47 Teng H W, Chen P M, Yang Y H, Gau J P. The prolonged activated partial thromboplastin time at diagnosis indicates less favorable prognosis in IgA myeloma.  Jpn J Clin Oncol. 2007;  37 (8) 609-614
    Google Scholar
  • 48 O'Kane M J, Wisdom G B, Desai Z R, Archbold G P. Inhibition of fibrin monomer polymerisation by myeloma immunoglobulin.  J Clin Pathol. 1994;  47 (3) 266-268
    Google Scholar
  • 49 Kotlín R, Sobotková A, Riedel T et al.. Acquired dysfibrinogenemia secondary to multiple myeloma.  Acta Haematol. 2008;  120 (2) 75-81
    Google Scholar
  • 50 Glueck H I, Hong R. A circulating anticoagulant in gamma-1A-multiple myeloma: its modification by penicillin.  J Clin Invest. 1965;  44 (11) 1866-1881
    Google Scholar
  • 51 Sallah S, Nguyen N P, Abdallah J M, Hanrahan L R. Acquired hemophilia in patients with hematologic malignancies.  Arch Pathol Lab Med. 2000;  124 (5) 730-734
    Google Scholar
  • 52 Franchini M, Targher G, Manzato F, Lippi G. Acquired factor VIII inhibitors in oncohematology: a systematic review.  Crit Rev Oncol Hematol. 2008;  66 (3) 194-199
    Google Scholar
  • 53 Sari I, Erkurt M A, Ifran A, Kaptan K, Beyan C. Multiple myeloma presenting with acquired factor VIII inhibitor.  Int J Hematol. 2009;  90 (2) 166-169
    Google Scholar
  • 54 Colwell N S, Tollefsen D M, Blinder M A. Identification of a monoclonal thrombin inhibitor associated with multiple myeloma and a severe bleeding disorder.  Br J Haematol. 1997;  97 (1) 219-226
    Google Scholar
  • 55 Holme P A, Brosstad F, Tjønnfjord G E. Acquired haemophilia: management of bleeds and immune therapy to eradicate autoantibodies.  Haemophilia. 2005;  11 (5) 510-515
    Google Scholar
  • 56 Llamas P, Outeiriño J, Espinoza J, Santos A B, Román A, Tomás J F. Report of three cases of circulating heparin-like anticoagulants.  Am J Hematol. 2001;  67 (4) 256-258
    Google Scholar
  • 57 Palmer R N, Rick M E, Rick P D, Zeller J A, Gralnick H R. Circulating heparan sulfate anticoagulant in a patient with a fatal bleeding disorder.  N Engl J Med. 1984;  310 (26) 1696-1699
    Google Scholar
  • 58 Goddard I R, Stewart W K, Hodson B A, Dawes J. Plasma exchange as a treatment for endogenous glycosaminoglycan anticoagulant induced haemorrhage in a patient with myeloma kidney.  Nephron. 1990;  56 (1) 94-96
    Google Scholar
  • 59 Torjemane L, Guermazi S, Ladeb S et al.. Heparin-like anticoagulant associated with multiple myeloma and neutralized with protamine sulfate.  Blood Coagul Fibrinolysis. 2007;  18 (3) 279-281
    Google Scholar
  • 60 Yood R A, Skinner M, Rubinow A, Talarico L, Cohen A S. Bleeding manifestations in 100 patients with amyloidosis.  JAMA. 1983;  249 (10) 1322-1324
    Google Scholar
  • 61 Gastineau D A, Gertz M A, Daniels T M, Kyle R A, Bowie E J. Inhibitor of the thrombin time in systemic amyloidosis: a common coagulation abnormality.  Blood. 1991;  77 (12) 2637-2640
    Google Scholar
  • 62 Gamba G, Montani N, Anesi E et al.. Clotting alterations in primary systemic amyloidosis.  Haematologica. 2000;  85 (3) 289-292
    Google Scholar
  • 63 Mumford A D, O'Donnell J, Gillmore J D, Manning R A, Hawkins P N, Laffan M. Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis.  Br J Haematol. 2000;  110 (2) 454-460
    Google Scholar
  • 64 Greipp P R, Kyle R A, Bowie E J. Factor-X deficiency in amyloidosis: a critical review.  Am J Hematol. 1981;  11 (4) 443-450
    Google Scholar
  • 65 Furie B, Greene E, Furie B C. Syndrome of acquired factor X deficiency and systemic amyloidosis in vivo studies of the metabolic fate of factor X.  N Engl J Med. 1977;  297 (2) 81-85
    Google Scholar
  • 66 Sane D C, Pizzo S V, Greenberg C S. Elevated urokinase-type plasminogen activator level and bleeding in amyloidosis: case report and literature review.  Am J Hematol. 1989;  31 (1) 53-57
    Google Scholar
  • 67 Liebman H A, Carfagno M K, Weitz I C et al.. Excessive fibrinolysis in amyloidosis associated with elevated plasma single-chain urokinase.  Am J Clin Pathol. 1992;  98 (5) 534-541
    Google Scholar
  • 68 Bouma B, Maas C, Hazenberg B P, Lokhorst H M, Gebbink M F. Increased plasmin-alpha2-antiplasmin levels indicate activation of the fibrinolytic system in systemic amyloidoses.  J Thromb Haemost. 2007;  5 (6) 1139-1142
    Google Scholar
  • 69 Rodrigues C A, Ferrarotto R, Kalil Filho R, Novis YAS, Hoff PMG. Venous thromboembolism and cancer: a systematic review.  J Thromb Thrombolysis. 2010;  30 (1) 67-78
    Google Scholar
  • 70 Goldhaber S Z. Risk factors for venous thromboembolism.  J Am Coll Cardiol. 2010;  56 (1) 1-7
    Google Scholar
  • 71 Bennet C L, Angelotta C, Yarnold P R et al.. Thalidomide- and lenalinomide-associated thromboembolism among patients with cancer.  JAMA. 2006;  296 (21) 2558-2560
    Google Scholar
  • 72 Bennett C L, Silver S M, Djulbegovic B et al.. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia.  JAMA. 2008;  299 (8) 914-924
    Google Scholar
  • 73 Katodritou E, Verrou E, Hadjiaggelidou C et al.. Erythropoiesis-stimulating agents are associated with reduced survival in patients with multiple myeloma.  Am J Hematol. 2008;  83 (9) 697-701
    Google Scholar
  • 74 Bohlius J, Schmidlin K, Brillant C et al.. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials.  Lancet. 2009;  373 (9674) 1532-1542
    Google Scholar
  • 75 Srkalovic G, Cameron M G, Rybicki L, Deitcher S R, Kattke-Marchant K, Hussein M A. Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease.  Cancer. 2004;  101 (3) 558-566
    Google Scholar
  • 76 Sallah S, Husain A, Wan J, Vos P, Nguyen N P. The risk of venous thromboembolic disease in patients with monoclonal gammopathy of undetermined significance.  Ann Oncol. 2004;  15 (10) 1490-1494
    Google Scholar
  • 77 Petropoulou A D, Gerotziafas G T, Samama M M, Hatmi M, Rendu F, Elalamy I. In vitro study of the hypercoagulable state in multiple myeloma patients treated or not with thalidomide.  Thromb Res. 2008;  121 (4) 493-497
    Google Scholar
  • 78 Carr Jr M E, Dent R M, Carr S L. Abnormal fibrin structure and inhibition of fibrinolysis in patients with multiple myeloma.  J Lab Clin Med. 1996;  128 (1) 83-88
    Google Scholar
  • 79 Yağci M, Sucak G T, Haznedar R. Fibrinolytic activity in multiple myeloma.  Am J Hematol. 2003;  74 (4) 231-237
    Google Scholar
  • 80 Tricot G. New insights into role of microenvironment in multiple myeloma.  Lancet. 2000;  355 (9200) 248-250
    Google Scholar
  • 81 Barillé S, Bataille R, Amiot M. The role of interleukin-6 and interleukin-6/interleukin-6 receptor-alpha complex in the pathogenesis of multiple myeloma.  Eur Cytokine Netw. 2000;  11 (4) 546-551
    Google Scholar
  • 82 Mechtcheriakova D, Wlachos A, Holzmüller H, Binder B R, Hofer E. Vascular endothelial cell growth factor-induced tissue factor expression in endothelial cells is mediated by EGR-1.  Blood. 1999;  93 (11) 3811-3823
    Google Scholar
  • 83 Amrani D L. Regulation of fibrinogen biosynthesis: glucocorticoid and interleukin-6 control.  Blood Coagul Fibrinolysis. 1990;  1 (4–5) 443-446
    Google Scholar
  • 84 Stirling D, Hannant W A, Ludlam C A. Transcriptional activation of the factor VIII gene in liver cell lines by interleukin-6.  Thromb Haemost. 1998;  79 (1) 74-78
    Google Scholar
  • 85 Auwerda JJA, Sonneveld P, de Maat MPM, Leebeek FWG. Prothrombotic coagulation abnormalities in patients with newly diagnosed multiple myeloma.  Haematologica. 2007;  92 (2) 279-280
    Google Scholar
  • 86 van Marion AMW, Auwerda JJA, Lisman T et al.. Prospective evaluation of coagulopathy in multiple myeloma patients before, during and after various chemotherapeutic regimens.  Leuk Res. 2008;  32 (7) 1078-1084
    Google Scholar
  • 87 Zangari M, Saghafifar F, Anaissie E et al.. Activated protein C resistance in the absence of factor V Leiden mutation is a common finding in multiple myeloma and is associated with an increased risk of thrombotic complications.  Blood Coagul Fibrinolysis. 2002;  13 (3) 187-192
    Google Scholar
  • 88 Elice F, Fink L, Tricot G, Barlogie B, Zangari M. Acquired resistance to activated protein C (aAPCR) in multiple myeloma is a transitory abnormality associated with an increased risk of venous thromboembolism.  Br J Haematol. 2006;  134 (4) 399-405
    Google Scholar
  • 89 Gruber A, Blaskó G, Sas G. Functional deficiency of protein C and skin necrosis in multiple myeloma.  Thromb Res. 1986;  42 (4) 579-581
    Google Scholar
  • 90 Deitcher S R, Erban J K, Limentani S A. Acquired free protein S deficiency associated with multiple myeloma: a case report.  Am J Hematol. 1996;  51 (4) 319-323
    Google Scholar
  • 91 Yasin Z, Quick D, Thiagarajan P, Spoor D, Caraveo J, Palascak J. Light-chain paraproteins with lupus anticoagulant activity.  Am J Hematol. 1999;  62 (2) 99-102
    Google Scholar
  • 92 Bellotti V, Gamba G, Merlini G et al.. Study of three patients with monoclonal gammopathies and ‘lupus-like’ anticoagulants.  Br J Haematol. 1989;  73 (2) 221-227
    Google Scholar
  • 93 Takamiya O, Machida S, Okuda M, Nojima J, Koreeda C, Kubara K. A non-immunological phospholipid-dependent coagulation inhibitor associated with IgGlambda-type multiple myeloma.  Am J Hematol. 2004;  75 (1) 34-39
    Google Scholar
  • 94 Swystun L L, Shin L Y, Beaudin S, Liaw P C. Chemotherapeutic agents doxorubicin and epirubicin induce a procoagulant phenotype on endothelial cells and blood monocytes.  J Thromb Haemost. 2009;  7 (4) 619-626
    Google Scholar
  • 95 Reddy K V, Bhattacharjee G, Schabbauer G et al.. Dexamethasone enhances LPS induction of tissue factor expression in human monocytic cells by increasing tissue factor mRNA stability.  J Leukoc Biol. 2004;  76 (1) 145-151
    Google Scholar
  • 96 Kerachian M A, Cournoyer D, Harvey E J et al.. Effect of high-dose dexamethasone on endothelial haemostatic gene expression and neutrophil adhesion.  J Steroid Biochem Mol Biol. 2009;  116 (3–5) 127-133
    Google Scholar
  • 97 van Giezen J J, Jansen J W. Correlation of in vitro and in vivo decreased fibrinolytic activity caused by dexamethasone.  Ann N Y Acad Sci. 1992;  667 199-201
    Google Scholar
  • 98 Arkel Y S, Ku D H, Thurston A L. The effect of thalidomide on tissue factor activity in Mono Mac 6 cells and the relationship to tumor necrosis factor (TNF)-alpha-stimulated cells.  J Thromb Haemost. 2003;  1 (12) 2691-2692
    Google Scholar
  • 99 Zangari M, Guerrero J, Cavallo F, Prasad H K, Esseltine D, Fink L. Hemostatic effects of bortezomib treatment in patients with relapsed or refractory multiple myeloma.  Haematologica. 2008;  93 (6) 953-954
    Google Scholar
  • 100 Hiroi T, Deming C B, 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
    Google Scholar
  • 101 Ghosh N, Ye X, Ferguson A, Huff C A, Borrello I. Bortezomib and thalidomide, a steroid free regimen in newly diagnosed patients with multiple myeloma.  Br J Haematol. 2011;  152 (5) 593-599
    Google Scholar
  • 102 Lackner H. Hemostatic abnormalities associated with dysproteinemias.  Semin Hematol. 1973;  10 (2) 125-133
    Google Scholar
  • 103 Glaspy J A. Hemostatic abnormalities in multiple myeloma and related disorders.  Hematol Oncol Clin North Am. 1992;  6 (6) 1301-1314
    Google Scholar
  • 104 Talamo G, Farooq U, Zangari M et al.. Beyond the CRAB symptoms: a study of presenting clinical manifestations of multiple myeloma.  Clin Lymphoma Myeloma Leuk. 2010;  10 (6) 464-468
    Google Scholar
  • 105 Kyrtsonis M C, Vassilakopoulos T P, Angelopoulou M K et al.. Waldenström's macroglobulinemia: clinical course and prognostic factors in 60 patients. Experience from a single hematology unit.  Ann Hematol. 2001;  80 (12) 722-727
    Google Scholar
  • 106 Kyle R A, Gertz M A. Primary systemic amyloidosis: clinical and laboratory features in 474 cases.  Semin Hematol. 1995;  32 (1) 45-59
    Google Scholar
  • 107 Ebert E C, Nagar M. Gastrointestinal manifestations of amyloidosis.  Am J Gastroenterol. 2008;  103 (3) 776-787
    Google Scholar
  • 108 Kim S H, Kang E J, Park J W et al.. Gastrointestinal amyloidosis presenting with multiple episodes of gastrointestinal bleeding.  Cardiovasc Intervent Radiol. 2009;  32 (3) 577-580
    Google Scholar
  • 109 Oluk M A, Murphy J. Nasopharyngeal amyloidosis: an unusual cause for epistaxis.  J Laryngol Otol. 2010;  124 (2) 209-212
    Google Scholar
  • 110 Morita Y, Yasuda M, Nakao M, Tsujimura Y, Isono M. Pulmonary hemorrhage and acute renal failure as an initial presentation of multiple myeloma.  Intern Med. 2010;  49 (14) 1401-1403
    Google Scholar
  • 111 Crowley R W, Sansur C A, Sheehan J P, Mandell J W, Kassell N F, Dumont A S. Intracranial plasmacytoma with apoplectic presentation and spontaneous intracerebral hemorrhage: Case report and review of the literature.  Clin Neurol Neurosurg. 2010;  112 (2) 172-175
    Google Scholar
  • 112 Oshima K, Kanda Y, Nannya Y et al.. Clinical and pathologic findings in 52 consecutively autopsied cases with multiple myeloma.  Am J Hematol. 2001;  67 (1) 1-5
    Google Scholar
  • 113 Franchini M, Lippi G. Acquired factor VIII inhibitors.  Blood. 2008;  112 (2) 250-255
    Google Scholar
  • 114 Collins P, Budde U, Rand J H, Federici A B, Kessler C M. Epidemiology and general guidelines of the management of acquired haemophilia and von Willebrand syndrome.  Haemophilia. 2008;  14 (Suppl 3) 49-55
    Google Scholar
  • 115 Franchini M. The use of recombinant activated factor VII in platelet disorders: a critical review of the literature.  Blood Transfus. 2009;  7 (1) 24-28
    Google Scholar
  • 116 De Simone C, Catalano L, Coppola A et al.. Acquired hemophilia: an early marker of relapse in a patient with a history of multiple myeloma.  Haematologica. 2004;  89 (Suppl 8) 145
    Google Scholar
  • 117 Boggio L, Green D. Recombinant human factor VIIa in the management of amyloid-associated factor X deficiency.  Br J Haematol. 2001;  112 (4) 1074-1075
    Google Scholar
  • 118 Mannucci P M, Levi M. Prevention and treatment of major blood loss.  N Engl J Med. 2007;  356 (22) 2301-2311
    Google Scholar
  • 119 Friederich P W, Wever P C, Briët E, Doorenbos C J, Levi M. Successful treatment with recombinant factor VIIa of therapy-resistant severe bleeding in a patient with acquired von Willebrand disease.  Am J Hematol. 2001;  66 (4) 292-294
    Google Scholar
  • 120 Smaradottir A, Bona R. A case of acquired von Willebrand syndrome successfully treated with recombinant Factor VIIa during thyroidectomy.  Thromb Haemost. 2004;  92 (5) 666-667 Correction in Thromb Haemost 2005; 93(5):1009
    Google Scholar
  • 121 Federici A B, Stabile F, Castaman G, Canciani M T, Mannucci P M. Treatment of acquired von Willebrand syndrome in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches.  Blood. 1998;  92 (8) 2707-2711
    Google Scholar
  • 122 Thompson C A, Kyle R, Gertz M, Heit J, Pruthi R, Pardanani A. Systemic AL amyloidosis with acquired factor X deficiency: A study of perioperative bleeding risk and treatment outcomes in 60 patients.  Am J Hematol. 2010;  85 (3) 171-173
    Google Scholar
  • 123 Zangari M, Tricot G, Polavaram L et al.. Survival effect of venous thromboembolism in patients with multiple myeloma treated with lenalidomide and high-dose dexamethasone.  J Clin Oncol. 2010;  28 (1) 132-135
    Google Scholar
  • 124 Carrier M, Le Gal G, Tay J, Wu C, Lee A Y. 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
    Google Scholar
  • 125 Verheul HMW, Pinedo H M. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition.  Nat Rev Cancer. 2007;  7 (6) 475-485
    Google Scholar
  • 126 Jagannath S, Barlogie B, Berenson J R SUMMIT/CREST Investigators et al. Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impared renal function.  Cancer. 2005;  103 (6) 1195-1200
    Google Scholar
  • 127 Raven W, Berghout A, van Houten A, Leebeek F W. Treatment of multiple myeloma and arterial thrombosis.  Ann Hematol. 2010;  89 (4) 419-420
    Google Scholar
  • 128 Libourel E J, Sonneveld P, van der Holt B, de Maat MPM, Leebeek FWG. High incidence of arterial thrombosis in young patients treated for multiple myeloma: results of a prospective cohort study.  Blood. 2010;  116 (1) 22-26
    Google Scholar
  • 129 Geerts W H, Bergqvist D, Pineo G F American College of Chest Physicians et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133 (6, Suppl) 381S-453S
    Google Scholar
  • 130 Palumbo A, Rajkumar S V, Dimopoulos M A International Myeloma Working Group et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma.  Leukemia. 2008;  22 (2) 414-423
    Google Scholar
  • 131 Musallam K M, Dahdaleh F S, Shamseddine A I, Taher A T. Incidence and prophylaxis of venous thromboembolic events in multiple myeloma patients receiving immunomodulatory therapy.  Thromb Res. 2009;  123 (5) 679-686
    Google Scholar
  • 132 Palumbo A, Davies F, Kropff M et al.. Consensus guidelines for the optimal management of adverse events in newly diagnosed, transplant-ineligible patients receiving melphalan and prednisone in combination with thalidomide (MPT) for the treatment of multiple myeloma.  Ann Hematol. 2010;  89 (8) 803-811
    Google Scholar
  • 133 Barlogie B, Tricot G, Anaissie E et al.. Thalidomide and hematopoietic-cell transplantation for multiple myeloma.  N Engl J Med. 2006;  354 (10) 1021-1030
    Google Scholar
  • 134 Zangari M, Barlogie B, Anaissie E et al.. Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation.  Br J Haematol. 2004;  126 (5) 715-721
    Google Scholar
  • 135 Palumbo A, Bringhen S, Caravita T Italian Multiple Myeloma Network, GIMEMA 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
    Google Scholar
  • 136 Minnema M C, Breitkreutz I, Auwerda J J et al.. Prevention of venous thromboembolism with low molecular-weight heparin in patients with multiple myeloma treated with thalidomide and chemotherapy.  Leukemia. 2004;  18 (12) 2044-2046
    Google Scholar
  • 137 Wang M, Weber D M, Delasalle K, Alexanian R. Thalidomide-dexamethasone as primary therapy for advanced multiple myeloma.  Am J Hematol. 2005;  79 (3) 194-197
    Google Scholar
  • 138 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
    Google Scholar
  • 139 Cavo M, Zamagni E, Tosi P Bologna 2002 study et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma.  Blood. 2005;  106 (1) 35-39
    Google Scholar
  • 140 Klein U, Kosely F, Hillengass J et al.. Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone.  Ann Hematol. 2009;  88 (1) 67-71
    Google Scholar
  • 141 Knop S, Gerecke C, Liebisch P et al.. Lenalidomide, adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: a report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom).  Blood. 2009;  113 (18) 4137-4143
    Google Scholar
  • 142 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
    Google Scholar
  • 143 Rajkumar S V, Hayman S R, Lacy M Q et al.. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma.  Blood. 2005;  106 (13) 4050-4053
    Google Scholar
  • 144 Palumbo A, Falco P, Corradini P GIMEMA–Italian Multiple Myeloma Network et al. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA—Italian Multiple Myeloma Network.  J Clin Oncol. 2007;  25 (28) 4459-4465
    Google Scholar

Antonio CoppolaM.D. 

Regional Reference Center for Coagulation Disorders

Federico II University Hospital, Via S. Pansini, 5 - Naples, Italy

Email: antocopp@unina.it

      >