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Semin Thromb Hemost 2021; 47(05): 569-580
DOI: 10.1055/s-0041-1725099
Review Article

Altered Fibrinolysis in Hematological Malignances

Søren Thorgaard Bønløkke
1   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
2   Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
,
Hans Beier Ommen
2   Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
3   Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
,
Anne-Mette Hvas
1   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
3   Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
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Abstract

Bleeding and thrombosis are well-known complications to hematological malignancies, and changes in fibrinolysis impact both these issues. In the present systematic review, we provide an overview and discussion of the current literature in regards to clinical manifestations, diagnosis, and treatment of altered fibrinolysis in patients suffering from hematological malignancies, beyond acute promyelocytic leukemia. We performed a systematic literature search employing the databases Pubmed, Embase, and Web of Science to identify original studies investigating fibrinolysis in hematological malignancies. Studies investigating fibrinolysis in acute promyelocytic leukemia or disseminated intravascular coagulation were excluded. We identified 32 studies fulfilling the inclusion criteria. A majority of the studies were published more than two decades ago, and none of the studies examined all available markers of fibrinolysis or used dynamic clot lysis assays. In acute leukemia L-asparaginase treatment induced a hypofibrinolytic state, and prior to chemotherapy there seemed to be little to no change in fibrinolysis. In studies examining fibrinolysis during chemotherapy results were ambiguous. Two studies examining multiple myeloma indicated hypofibrinolysis prior to chemotherapy, and in another plasma cell disease, amyloid light chain-amyloidosis, clear signs of hyperfibrinolysis were demonstrated. In myeloproliferative neoplasms, the studies reported signs of hypofibrinolysis, in line with the increased risk of thrombosis in this disease. Only one study regarding lymphoma was identified, which indicated no alterations in fibrinolysis. In conclusion, this systematic review demonstrated that only sparse, and mainly old, evidence exists on fibrinolysis in hematological malignancy. However, the published studies showed a tendency toward hypofibrinolysis in myeloproliferative disorders, an increased risk of hyperfibrinolysis, and bleeding in patients with AL-amyloidosis, whereas studies regarding acute leukemias were inconclusive except with regard to L-asparaginase treatment, which induced a hypofibrinolytic state.

Keywords

neoplasms - hematological malignancy - fibrinolysis - bleeding - thrombosis


Publication History

Article published online:
31 May 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Sant M, Allemani C, Tereanu C. et al; HAEMACARE Working Group. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood 2010; 116 (19) 3724-3734
    CrossrefPubMedSearch in Google Scholar
  • 2 Huang D, Yang Y, Sun J. et al. Annexin A2-S100A10 heterotetramer is upregulated by PML/RARα fusion protein and promotes plasminogen-dependent fibrinolysis and matrix invasion in acute promyelocytic leukemia. Front Med 2017; 11 (03) 410-422
    CrossrefPubMedSearch in Google Scholar
  • 3 Liu Y, Myrvang HK, Dekker LV. Annexin A2 complexes with S100 proteins: structure, function and pharmacological manipulation. Br J Pharmacol 2015; 172 (07) 1664-1676
    CrossrefPubMedSearch in Google Scholar
  • 4 Coppola A, Tufano A, Di Capua M, Franchini M. Bleeding and thrombosis in multiple myeloma and related plasma cell disorders. Semin Thromb Hemost 2011; 37 (08) 929-945
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Colombo R, Gallipoli P, Castelli R. Thrombosis and hemostatic abnormalities in hematological malignancies. Clin Lymphoma Myeloma Leuk 2014; 14 (06) 441-450
    CrossrefPubMedSearch in Google Scholar
  • 6 Franchini M, Mannucci PM. Primary hyperfibrinolysis: Facts and fancies. Thromb Res 2018; 166: 71-75
    CrossrefPubMedSearch in Google Scholar
  • 7 Winther-Larsen A, Sandfeld-Paulsen B, Hvas A-M. Hyperfibrinolysis in patients with solid malignant neoplasms: a systematic review. Semin Thromb Hemost 2020;
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Yağci M, Sucak GT, Haznedar R. Fibrinolytic activity in multiple myeloma. Am J Hematol 2003; 74 (04) 231-237
    CrossrefPubMedSearch in Google Scholar
  • 9 van Marion AMW, Auwerda JJA, Minnema MC. et al. Hypofibrinolysis during induction treatment of multiple myeloma may increase the risk of venous thrombosis. Thromb Haemost 2005; 94 (06) 1341-1343
    Thieme ConnectPubMedSearch in Google Scholar
  • 10 Liberati A, Altman DG, Tetzlaff J. et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009; 6 (07) e1000100
    CrossrefPubMedSearch in Google Scholar
  • 11 Cetkovsky P, Koza V, Cepelak V, Vit L, Sigutova P. Hemostatic changes in patients with acute lymphoblastic-leukemia during and after remission induction therapy. Fibrinolysis 1993; 7 (06) 386-390
    CrossrefPubMedSearch in Google Scholar
  • 12 Zurborn KH, Gram J, Glander K. et al. Influence of cytostatic treatment on the coagulation system and fibrinolysis in patients with non-Hodgkin's lymphomas and acute leukemias. Eur J Haematol 1991; 47 (01) 55-59
    CrossrefPubMedSearch in Google Scholar
  • 13 Bratt G, Blombäck M, Lockner D. Factors and inhibitors of blood coagulation and fibrinolysis in promyelocytic leukemia. Scand J Clin Lab Invest Suppl 1985; 178: 81-83
    PubMedSearch in Google Scholar
  • 14 Brakman P, Snyder J, Henderson ES, Astrup T. Blood coagulation and fibrinolysis in acute leukaemia. Br J Haematol 1970; 18 (02) 135-145
    CrossrefPubMedSearch in Google Scholar
  • 15 Ishihara T, Nogami K, Ochi S. et al. Disordered hemostasis associated with severely depressed fibrinolysis demonstrated using a simultaneous thrombin and plasmin generation assay during L-asparaginase induction therapy in pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer 2020; 67 (01) e28016
    CrossrefPubMedSearch in Google Scholar
  • 16 Sehgal S, Sharma S, Chandra J, Nangia A. Coagulation profile at diagnosis in patients with acute lymphoblastic leukemia. Indian J Pediatr 2016; 83 (10) 1082-1086
    CrossrefPubMedSearch in Google Scholar
  • 17 Albayrak M, Gürsel T, Kaya Z, Koçak U. Alterations in procoagulant, anticoagulant, and fibrinolytic systems before and after start of induction chemotherapy in children with acute lymphoblastic leukemia. Clin Appl Thromb Hemost 2013; 19 (06) 644-651
    CrossrefPubMedSearch in Google Scholar
  • 18 Cetkovský P, Koza V, Čepelák V, Vít L. Haemostasis in patients with acute myeloid leukaemia treated with intermediate dose of cytosine arabinoside and mitoxantrone: the influence of chemotherapy, infection and remission status on haemostasis. Fibrinolysis 1995; 9 (03) 165-169
    CrossrefPubMedSearch in Google Scholar
  • 19 Vellenga E, Kluft C, Mulder NH, Wijngaards G, Nieweg HO. The influence of L-asparaginase therapy on the fibrinolytic system. Br J Haematol 1984; 57 (02) 247-254
    CrossrefPubMedSearch in Google Scholar
  • 20 Ishiguro K, Hayashi T, Yokoyama Y. et al. Elevation of plasmin-α2-plasmin inhibitor complex predicts the diagnosis of systemic AL amyloidosis in patients with monoclonal protein. Intern Med 2018; 57 (06) 783-788
    CrossrefPubMedSearch in Google Scholar
  • 21 Balcik OS, Albayrak M, Uyar ME. et al. Serum thrombin activatable fibrinolysis inhibitor levels in patients with newly diagnosed multiple myeloma. Blood Coagul Fibrinolysis 2011; 22 (04) 260-263
    CrossrefPubMedSearch in Google Scholar
  • 22 Uchiba M, Imamura T, Hata H. et al. Excessive fibrinolysis in AL-amyloidosis is induced by urokinae-type plasminogen activator from bone marrow plasma cells. Amyloid 2009; 16 (02) 89-93
    CrossrefPubMedSearch in Google Scholar
  • 23 Gadomska G, Rość D, Stankowska K, Boinska J, Ruszkowska-Ciastek B, Wieczór R. Selected parameters of hemostasis in patients with myeloproliferative neoplasms. Blood Coagul Fibrinolysis 2014; 25 (05) 464-470
    CrossrefPubMedSearch in Google Scholar
  • 24 Rusak T, Piszcz J, Misztal T, Brańska-Januszewska J, Tomasiak M. Platelet-related fibrinolysis resistance in patients suffering from PV. Impact of clot retraction and isovolemic erythrocytapheresis. Thromb Res 2014; 134 (01) 192-198
    CrossrefPubMedSearch in Google Scholar
  • 25 Sonmez M, Saglam F, Karahan SC. et al. Treatment related changes in antifibrinolytic activity in patients with polycythemia vera. Hematology 2010; 15 (06) 391-396
    CrossrefPubMedSearch in Google Scholar
  • 26 Rość D, Kremplewska-Nalezyta E, Gadomska G, Zastawna E, Michalski A, Drewniak W. Plasminogen activators (t-PA and u-PA) and plasminogen activators inhibitors (PAI-1 and PAI-2) in some myeloproliferative syndromes. Med Sci Monit 2000; 6 (04) 684-691
    PubMedSearch in Google Scholar
  • 27 Lugassy G, Filin I. Study of fibrinolytic parameters in different types of polycythemia. Am J Hematol 1999; 60 (03) 196-199
    CrossrefPubMedSearch in Google Scholar
  • 28 Pósán E, Ujj G, Kiss A, Telek B, Rák K, Udvardy M. Reduced in vitro clot lysis and release of more active platelet PAI-1 in polycythemia vera and essential thrombocythemia. Thromb Res 1998; 90 (02) 51-56
    CrossrefPubMedSearch in Google Scholar
  • 29 Morishita E, Saito M, Asakura H. et al. Increased levels of plasma thrombomodulin in chronic myelogenous leukemia. Am J Hematol 1992; 39 (03) 183-187
    CrossrefPubMedSearch in Google Scholar
  • 30 Wieczorek I, MacGregor IR, Prescott RJ, Ludlam CA. The fibrinolytic system and proteins C and S in treated polycythaemia rubra vera. Blood Coagul Fibrinolysis 1992; 3 (06) 823-826
    CrossrefPubMedSearch in Google Scholar
  • 31 Stathakis NE, Papayannis AG, Arapakis G, Gardikas C. Haemostatic defects in polycythaemia vera. Blut 1974; 29 (02) 77-86
    CrossrefPubMedSearch in Google Scholar
  • 32 Undas A, Zubkiewicz-Usnarska L, Helbig G. et al. Altered plasma fibrin clot properties and fibrinolysis in patients with multiple myeloma. Eur J Clin Invest 2014; 44 (06) 557-566
    CrossrefPubMedSearch in Google Scholar
  • 33 Meyer K, Williams EC. Fibrinolysis and acquired alpha-2 plasmin inhibitor deficiency in amyloidosis. Am J Med 1985; 79 (03) 394-396
    CrossrefPubMedSearch in Google Scholar
  • 34 Gafter U, Mandel EM, Weiss S, Djaldetti M. Primary fibrinolysis and spontaneous rupture of the spleen in acute lymphoblastic leukemia. Acta Haematol 1976; 56 (06) 355-359
    CrossrefPubMedSearch in Google Scholar
  • 35 Vellenga E, van Imhoff GW, Sterrenberg L, Kluft C. Acute lymphocytic leukaemia complicated by hypofibrinogenaemia without evidence for impaired fibrinogen synthesis or disseminated intravascular coagulation. Acta Haematol 1983; 69 (06) 419-421
    CrossrefPubMedSearch in Google Scholar
  • 36 Millard LG, Rowell NR. Primary amyloidosis and myelomatosis associated with excessive fibrinolytic activity. Br J Dermatol 1976; 94 (05) 569-571
    CrossrefPubMedSearch in Google Scholar
  • 37 Talarico L, Weintraub LR. Leukocytic fibrinolysis in myelomonocytic leukemia. Cancer 1977; 39 (04) 1618-1624
    CrossrefPubMedSearch in Google Scholar
  • 38 Van Slyck EJ, Raman SB, Janakiraman N. Primary fibrinolysis in acute monocytic leukemia. Henry Ford Hosp Med J 1989; 37 (01) 33-36
    PubMedSearch in Google Scholar
  • 39 Liebman H, Chinowsky M, Valdin J, Kenoyer G, Feinstein D. Increased fibrinolysis and amyloidosis. Arch Intern Med 1983; 143 (04) 678-682
    CrossrefPubMedSearch in Google Scholar
  • 40 Matsumoto T, Nogami K, Shima M. Simultaneous measurement of thrombin and plasmin generation to assess the interplay between coagulation and fibrinolysis. Thromb Haemost 2013; 110 (04) 761-768
    Thieme ConnectPubMedSearch in Google Scholar
  • 41 Zurborn KH, Duscha H, Gram J, Bruhn HD. Investigations of coagulation system and fibrinolysis in patients with disseminated adenocarcinomas and non-Hodgkin's lymphomas. Oncology 1990; 47 (05) 376-380
    CrossrefPubMedSearch in Google Scholar
  • 42 Smalberg JH, Kruip MJ, Janssen HL, Rijken DC, Leebeek FW, de Maat MP. Hypercoagulability and hypofibrinolysis and risk of deep vein thrombosis and splanchnic vein thrombosis: similarities and differences. Arterioscler Thromb Vasc Biol 2011; 31 (03) 485-493
    CrossrefPubMedSearch in Google Scholar
  • 43 Petrova OYu, Sukhanov VA, Levit DA. Hypofibrinolysis as a major factor risk of thromboembolic events in cancer patients. Malignant Tumours 2015; 0 (03) 147-154
    CrossrefPubMedSearch in Google Scholar
  • 44 Goyal G, Bhatt VR. L-asparaginase and venous thromboembolism in acute lymphocytic leukemia. Future Oncol 2015; 11 (17) 2459-2470
    CrossrefPubMedSearch in Google Scholar
  • 45 Hasegawa D, Imamura T, Yumura-Yagi K. et al; Japan Association of Childhood Leukemia Study Group (JACLS). Risk-adjusted therapy for pediatric non-T cell ALL improves outcomes for standard risk patients: results of JACLS ALL-02. Blood Cancer J 2020; 10 (02) 23
    CrossrefPubMedSearch in Google Scholar
  • 46 Möricke A, Reiter A, Zimmermann M. et al; German-Austrian-Swiss ALL-BFM Study Group. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 2008; 111 (09) 4477-4489
    CrossrefPubMedSearch in Google Scholar
  • 47 Palumbo A, Palladino C. Venous and arterial thrombotic risks with thalidomide: evidence and practical guidance. Ther Adv Drug Saf 2012; 3 (05) 255-266
    CrossrefPubMedSearch in Google Scholar
  • 48 Hjertner O, Qvigstad G, Hjorth-Hansen H. et al. Expression of urokinase plasminogen activator and the urokinase plasminogen activator receptor in myeloma cells. Br J Haematol 2000; 109 (04) 815-822
    CrossrefPubMedSearch in Google Scholar
  • 49 Cesarman-Maus G, Braggio E, Fonseca R. Thrombosis in multiple myeloma (MM). Hematology 2012; 17 (01, Suppl 1): S177-S180
    CrossrefPubMedSearch in Google Scholar
  • 50 Shou L-H, Cao D, Dong X-H, Fang Q, Xu B-L, Fei J-P. Bone marrow urokinase plasminogen activator receptor levels are associated with the progress of multiple myeloma. Chin Med Sci J 2016; 31 (03) 155-160
    CrossrefPubMedSearch in Google Scholar
  • 51 Hecht M, von Metzler I, Sack K, Kaiser M, Sezer O. Interactions of myeloma cells with osteoclasts promote tumour expansion and bone degradation through activation of a complex signalling network and upregulation of cathepsin K, matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA). Exp Cell Res 2008; 314 (05) 1082-1093
    CrossrefPubMedSearch in Google Scholar
  • 52 Sucker C, Hetzel GR, Grabensee B, Stockschlaeder M, Scharf RE. Amyloidosis and bleeding: pathophysiology, diagnosis, and therapy. Am J Kidney Dis 2006; 47 (06) 947-955
    CrossrefPubMedSearch in Google Scholar
  • 53 Halligan CS, Lacy MQ, Vincent Rajkumar S. et al. Natural history of thromboembolism in AL amyloidosis. Amyloid 2006; 13 (01) 31-36
    CrossrefPubMedSearch in Google Scholar
  • 54 Brown JD, Adams VR. Incidence and risk factors of thromboembolism with multiple myeloma in the presence of death as a competing risk: an empirical comparison of statistical methodologies. Healthcare (Basel) 2016; 4 (01) E16
    CrossrefPubMedSearch in Google Scholar
  • 55 Falanga A, Marchetti M. Thrombosis in myeloproliferative neoplasms. Semin Thromb Hemost 2014; 40 (03) 348-358
    Thieme ConnectPubMedSearch in Google Scholar
  • 56 Neergaard-Petersen S, Mogensen VB, Veirup MS, Grove EL, Kristensen SD, Hvas A-M. Fibrin clot lysis assay: establishment of a reference interval. Thromb Res 2018; 167: 9-11
    CrossrefPubMedSearch in Google Scholar
  • 57 Larsen JB, Hvas A-M. Fibrin clot formation and lysis in plasma. Methods Protoc 2020; 3 (04) E67
    CrossrefPubMedSearch in Google Scholar
  • 58 Lisman T, Leebeek FW, Mosnier LO. et al. Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis. Gastroenterology 2001; 121 (01) 131-139
    CrossrefPubMedSearch in Google Scholar