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CC BY 4.0 · TH Open 2019; 03(02): e165-e170
DOI: 10.1055/s-0039-1692204
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Emerging Factors Implicated in Fibrotic Organ–Associated Thrombosis: The Case of Two Organs

Orly Leiva    *
1   Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States
2   Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States
,
Roelof H. Bekendam   *
1   Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States
,
Brenda D. Garcia
1   Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States
3   Department of Medicine, Mount Auburn Hospital and Harvard Medical School, Boston, Massachusetts, United States
,
Cristal Thompson
1   Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States
4   Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States
,
Alan Cantor
5   Children's Hospital Boston, Boston, Massachusetts, United States
,
Vipul Chitalia
1   Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States
4   Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States
6   VA Boston Healthcare System, Boston, Massachusetts, United States
,
Katya Ravid
1   Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States
4   Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States
› Author Affiliations Funding This work was funded in part by NHLBI R01HL136363 and NIH R01HL080442 (K.R.), NIH R01HL132325 and R01CA175382 (V.C.C.), and the Thrombosis and Hemostasis Affinity Research Collaborative (ARC0 funded by the Evans Center for Interdisciplinary Biomedical Research).
Further Information

Publication History

11 February 2019

30 April 2019

Publication Date:
07 June 2019 (online)

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Abstract

Thrombosis is at the heart of cardiovascular complications observed in specific diseases. A heightened thrombosis risk above that in general population in diseases such as myelofibrosis and chronic kidney disease implicates disease-specific mediators of thrombosis. This relative lack of information regarding the mechanisms of thrombosis in specific organ pathologies hitherto has remained limited. Evolving literature implicates some soluble factors in the blood of patients with discrete disorders, inflicting fundamental changes in the components of thrombosis. In this era of precision medicine, integrating these disease-specific factors in a comprehensive thrombotic risk assessment of patients is imperative in guiding therapeutic decisions. A complex network of mechanisms regulates each organ pathology and resultant thrombotic phenotypes. This review surveys different effectors of thrombogenicity associated with two pathologically fibrotic organs used as model systems, the bone marrow and kidney, as well as focuses attention to a common inducer of fibrosis and thrombosis, lysyl oxidase.

Keywords

thrombosis - myelofibrosis - chronic kidney disease - lysyl oxidase - fibrosis

* These authors contributed equally.


 

  • References

  • 1 Leiva O, Ng SK, Chitalia S, Balduini A, Matsuura S, Ravid K. The role of the extracellular matrix in primary myelofibrosis. Blood Cancer J 2017; 7 (02) e525
    CrossrefPubMedGoogle Scholar
  • 2 Tefferi A, Pardanani A. Myeloproliferative neoplasms: a contemporary review. JAMA Oncol 2015; 1 (01) 97-105
    CrossrefPubMedGoogle Scholar
  • 3 Falanga A, Marchetti M. Thrombosis in myeloproliferative neoplasms. Semin Thromb Hemost 2014; 40 (03) 348-358
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Barbui T, Carobbio A, Cervantes F. , et al. Thrombosis in primary myelofibrosis: incidence and risk factors. Blood 2010; 115 (04) 778-782
    CrossrefPubMedGoogle Scholar
  • 5 Kc D, Falchi L, Verstovsek S. The underappreciated risk of thrombosis and bleeding in patients with myelofibrosis: a review. Ann Hematol 2017; 96 (10) 1595-1604
    CrossrefPubMedGoogle Scholar
  • 6 Rupoli S, Goteri G, Picardi P. , et al. Thrombosis in essential thrombocytemia and early/prefibrotic primary myelofibrosis: the role of the WHO histological diagnosis. Diagn Pathol 2015; 10: 29-36
    CrossrefPubMedGoogle Scholar
  • 7 Rungjirajittranon T, Owattanapanich W, Ungprasert P, Siritanaratkul N, Ruchutrakool T. A systematic review and meta-analysis of the prevalence of thrombosis and bleeding at diagnosis of Philadelphia-negative myeloproliferative neoplasms. BMC Cancer 2019; 19 (01) 184-192
    CrossrefPubMedGoogle Scholar
  • 8 Woo KT, Choong HL, Wong KS, Tan HB, Chan CM. The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney Int 2012; 81 (10) 1044-1045
    CrossrefPubMedGoogle Scholar
  • 9 Hill NR, Fatoba ST, Oke JL. , et al. Global prevalence of chronic kidney disease - a systematic review and meta-analysis. PLoS One 2016; 11 (07) e0158765
    CrossrefPubMedGoogle Scholar
  • 10 Wattanakit K, Cushman M. Chronic kidney disease and venous thromboembolism: epidemiology and mechanisms. Curr Opin Pulm Med 2009; 15 (05) 408-412
    CrossrefPubMedGoogle Scholar
  • 11 Ocak G, Vossen CY, Rotmans JI. , et al. Venous and arterial thrombosis in dialysis patients. Thromb Haemost 2011; 106 (06) 1046-1052
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Arber DA, Orazi A, Hasserjian R. , et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127 (20) 2391-2405
    CrossrefPubMedGoogle Scholar
  • 13 Bertozzi I, Bogoni G, Biagetti G. , et al. Thromboses and hemorrhages are common in MPN patients with high JAK2V617F allele burden. Ann Hematol 2017; 96 (08) 1297-1302
    CrossrefPubMedGoogle Scholar
  • 14 Pei YQ, Wu Y, Wang F, Cui W. Prognostic value of CALR vs. JAK2V617F mutations on splenomegaly, leukemic transformation, thrombosis, and overall survival in patients with primary fibrosis: a meta-analysis. Ann Hematol 2016; 95 (09) 1391-1398
    CrossrefPubMedGoogle Scholar
  • 15 Lamrani L, Lacout C, Ollivier V. , et al. Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm. Blood 2014; 124 (07) 1136-1145
    PubMedGoogle Scholar
  • 16 Etheridge SL, Roh ME, Cosgrove ME. , et al. JAK2V617F-positive endothelial cells contribute to clotting abnormalities in myeloproliferative neoplasms. Proc Natl Acad Sci U S A 2014; 111 (06) 2295-2300
    CrossrefPubMedGoogle Scholar
  • 17 Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New fundamentals in hemostasis. Physiol Rev 2013; 93 (01) 327-358
    CrossrefPubMedGoogle Scholar
  • 18 Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359 (09) 938-949
    CrossrefPubMedGoogle Scholar
  • 19 Watson SP. Collagen receptor signaling in platelets and megakaryocytes. Thromb Haemost 1999; 82 (02) 365-376
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Hollopeter G, Jantzen HM, Vincent D. , et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409 (6817): 202-207
    CrossrefPubMedGoogle Scholar
  • 21 Wang Y, Gallant RC, Ni H. Extracellular matrix proteins in the regulation of thrombus formation. Curr Opin Hematol 2016; 23 (03) 280-287
    CrossrefPubMedGoogle Scholar
  • 22 Xu XR, Carrim N, Neves MA. , et al. Platelets and platelet adhesion molecules: novel mechanisms of thrombosis and anti-thrombotic therapies. Thromb J 2016; 14 (Suppl. 01) 29-38
    CrossrefPubMedGoogle Scholar
  • 23 Farndale RW, Sixma JJ, Barnes MJ, de Groot PG. The role of collagen in thrombosis and hemostasis. J Thromb Haemost 2004; 2 (04) 561-573
    CrossrefPubMedGoogle Scholar
  • 24 Angiolillo DJ, Ueno M, Goto S. Basic principles of platelet biology and clinical implications. Circ J 2010; 74 (04) 597-607
    CrossrefPubMedGoogle Scholar
  • 25 Moroi M, Jung SM, Okuma M, Shinmyozu K. A patient with platelets deficient in glycoprotein VI that lack both collagen-induced aggregation and adhesion. J Clin Invest 1989; 84 (05) 1440-1445
    CrossrefPubMedGoogle Scholar
  • 26 Kunicki TJ, Ruggeri ZM. Platelet collagen receptors and risk prediction in stroke and coronary artery disease. Circulation 2001; 104 (13) 1451-1453
    CrossrefPubMedGoogle Scholar
  • 27 Santoso S, Kunicki TJ, Kroll H, Haberbosch W, Gardemann A. Association of the platelet glycoprotein Ia C807T gene polymorphism with nonfatal myocardial infarction in younger patients. Blood 1999; 93 (08) 2449-2453
    CrossrefPubMedGoogle Scholar
  • 28 Moshfegh K, Wuillemin WA, Redondo M. , et al. Association of two silent polymorphisms of platelet glycoprotein Ia/IIa receptor with risk of myocardial infarction: a case-control study. Lancet 1999; 353 (9150): 351-354
    CrossrefPubMedGoogle Scholar
  • 29 Carlsson LE, Santoso S, Spitzer C, Kessler C, Greinacher A. The alpha2 gene coding sequence T807/A873 of the platelet collagen receptor integrin alpha2beta1 might be a genetic risk factor for the development of stroke in younger patients. Blood 1999; 93 (11) 3583-3586
    CrossrefPubMedGoogle Scholar
  • 30 Dodson PM, Haynes J, Starczynski J. , et al. The platelet glycoprotein Ia/IIa gene polymorphism C807T/G873A: a novel risk factor for retinal vein occlusion. Eye (Lond) 2003; 17 (06) 772-777
    CrossrefPubMedGoogle Scholar
  • 31 Roest M, Banga JD, Grobbee DE. , et al. Homozygosity for 807 T polymorphism in alpha(2) subunit of platelet alpha(2)beta(1) is associated with increased risk of cardiovascular mortality in high-risk women. Circulation 2000; 102 (14) 1645-1650
    CrossrefPubMedGoogle Scholar
  • 32 Bigalke B, Stellos K, Geisler T, Lindemann S, May AE, Gawaz M. Glycoprotein VI as a prognostic biomarker for cardiovascular death in patients with symptomatic coronary artery disease. Clin Res Cardiol 2010; 99 (04) 227-233
    CrossrefPubMedGoogle Scholar
  • 33 Alvarez-Larrán A, Arellano-Rodrigo E, Reverter JC. , et al. Increased platelet, leukocyte, and coagulation activation in primary myelofibrosis. Ann Hematol 2008; 87 (04) 269-276
    CrossrefPubMedGoogle Scholar
  • 34 Gremmel T, Gisslinger B, Gisslinger H, Panzer S. Response to aspirin therapy in patients with myeloproliferative neoplasms depends on the platelet count. Transl Res 2018; 200: 35-42
    CrossrefPubMedGoogle Scholar
  • 35 Guadall A, Lesteven E, Letort G. , et al. Endothelial cells harbouring the JAK2V617F mutation display pro-adherent and pro-thrombotic features. Thromb Haemost 2018; 118 (09) 1586-1599
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Guy A, Gourdou-Latyszenok V, Le Lay N. , et al. Vascular endothelial cell expression of JAK2V617F is sufficient to promote a pro-thrombotic state due to increased P-selectin expression. Haematologica 2019; 104 (01) 70-81
    CrossrefPubMedGoogle Scholar
  • 37 Kogan I, Chap D, Hoffman R, Axelman E, Brenner B, Nadir Y. JAK-2 V617F mutation increases heparanase procoagulant activity. Thromb Haemost 2016; 115 (01) 73-80
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Nadir Y, Brenner B, Zetser A. , et al. Heparanase induces tissue factor expression in vascular endothelial and cancer cells. J Thromb Haemost 2006; 4 (11) 2443-2451
    CrossrefPubMedGoogle Scholar
  • 39 Edelmann B, Gupta N, Schnoeder TM. , et al. JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation. J Clin Invest 2018; 128 (10) 4359-4371
    CrossrefPubMedGoogle Scholar
  • 40 Barosi G, Massa M, Campanelli R. , et al. Primary myelofibrosis: older age and high JAK2V617F allele burden are associated with elevated plasma high-sensitivity C-reactive protein levels and a phenotype of progressive disease. Leuk Res 2017; 60: 18-23
    CrossrefPubMedGoogle Scholar
  • 41 Augello C, Cattaneo D, Bucelli C. , et al. CD18 promoter methylation is associated with a higher risk of thrombotic complications in primary myelofibrosis. Ann Hematol 2016; 95 (12) 1965-1969
    CrossrefPubMedGoogle Scholar
  • 42 Abbonante V, Chitalia V, Rosti V. , et al. Upregulation of lysyl oxidase and adhesion to collagen of human megakaryocytes and platelets in primary myelofibrosis. Blood 2017; 130 (06) 829-831
    CrossrefPubMedGoogle Scholar
  • 43 Papadantonakis N, Matsuura S, Ravid K. Megakaryocyte pathology and bone marrow fibrosis: the lysyl oxidase connection. Blood 2012; 120 (09) 1774-1781
    PubMedGoogle Scholar
  • 44 Eliades A, Papadantonakis N, Bhupatiraju A. , et al. Control of megakaryocyte expansion and bone marrow fibrosis by lysyl oxidase. J Biol Chem 2011; 286 (31) 27630-27638
    CrossrefPubMedGoogle Scholar
  • 45 Matsuura S, Mi R, Koupenova M. , et al. Lysyl oxidase is associated with increased thrombosis and platelet reactivity. Blood 2016; 127 (11) 1493-1501
    CrossrefPubMedGoogle Scholar
  • 46 Anavekar NS, Pfeffer MA. Cardiovascular risk in chronic kidney disease. Kidney Int Suppl 2004; (92) S11-S15
    PubMedGoogle Scholar
  • 47 Abboud H, Henrich WL. Clinical practice. Stage IV chronic kidney disease. N Engl J Med 2010; 362 (01) 56-65
    CrossrefPubMedGoogle Scholar
  • 48 Best PJ, Lennon R, Ting HH. , et al. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 2002; 39 (07) 1113-1119
    CrossrefPubMedGoogle Scholar
  • 49 Jain N, Li X, Adams-Huet B. , et al. Differences in whole blood platelet aggregation at baseline and in response to aspirin and aspirin plus clopidogrel in patients with versus without chronic kidney disease. Am J Cardiol 2016; 117 (04) 656-663
    CrossrefPubMedGoogle Scholar
  • 50 Gremmel T, Müller M, Steiner S. , et al. Chronic kidney disease is associated with increased platelet activation and poor response to antiplatelet therapy. Nephrol Dial Transplant 2013; 28 (08) 2116-2122
    CrossrefPubMedGoogle Scholar
  • 51 Addi T, Dou L, Burtey S. Tryptophan-derived uremic toxins and thrombosis in chronic kidney disease. Toxins (Basel) 2018; 10 (10) E412
    CrossrefPubMedGoogle Scholar
  • 52 Casserly LF, Dember LM. Thrombosis in end-stage renal disease. Semin Dial 2003; 16 (03) 245-256
    CrossrefPubMedGoogle Scholar
  • 53 Jain N, Hedayati SS, Sarode R, Banerjee S, Reilly RF. Antiplatelet therapy in the management of cardiovascular disease in patients with CKD: what is the evidence?. Clin J Am Soc Nephrol 2013; 8 (04) 665-674
    CrossrefPubMedGoogle Scholar
  • 54 Tanios BY, Itani HS, Zimmerman DL. Clopidogrel use in end-stage kidney disease. Semin Dial 2015; 28 (03) 276-281
    CrossrefPubMedGoogle Scholar
  • 55 Aradi D, Komócsi A, Vorobcsuk A. , et al. Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: systematic review and meta-analysis. Am Heart J 2010; 160 (03) 543-551
    CrossrefPubMedGoogle Scholar
  • 56 Polzin A, Dannenberg L, Sansone R. , et al. Antiplatelet effects of aspirin in chronic kidney disease patients. J Thromb Haemost 2016; 14 (02) 375-380
    CrossrefPubMedGoogle Scholar
  • 57 Shashar M, Belghasem ME, Matsuura S. , et al. Targeting STUB1-tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk. Sci Transl Med 2017; 9 (417) eaam8475
    CrossrefPubMedGoogle Scholar
  • 58 Meijers BK, Evenepoel P. The gut-kidney axis: indoxyl sulfate, p-cresyl sulfate and CKD progression. Nephrol Dial Transplant 2011; 26 (03) 759-761
    CrossrefPubMedGoogle Scholar
  • 59 Yang K, Du C, Wang X. , et al. Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease-associated thrombosis in mice. Blood 2017; 129 (19) 2667-2679
    CrossrefPubMedGoogle Scholar
  • 60 Yang K, Nie L, Huang Y. , et al. Amelioration of uremic toxin indoxyl sulfate-induced endothelial cell dysfunction by Klotho protein. Toxicol Lett 2012; 215 (02) 77-83
    CrossrefPubMedGoogle Scholar
  • 61 Kolachalama VB, Shashar M, Alousi F. , et al. Uremic solute-aryl hydrocarbon receptor-tissue factor axis associates with thrombosis after vascular injury in humans. J Am Soc Nephrol 2018; 29 (03) 1063-1072
    CrossrefPubMedGoogle Scholar
  • 62 Gondouin B, Cerini C, Dou L. , et al. Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway. Kidney Int 2013; 84 (04) 733-744
    CrossrefPubMedGoogle Scholar
  • 63 Holy EW, Tanner FC. Tissue factor in cardiovascular disease pathophysiology and pharmacological intervention. Adv Pharmacol 2010; 59: 259-292
    CrossrefPubMedGoogle Scholar
  • 64 Steffel J, Lüscher TF, Tanner FC. Tissue factor in cardiovascular diseases: molecular mechanisms and clinical implications. Circulation 2006; 113 (05) 722-731
    CrossrefPubMedGoogle Scholar
  • 65 Shimizu H, Hirose Y, Nishijima F, Tsubakihara Y, Miyazaki H. ROS and PDGF-beta [corrected] receptors are critically involved in indoxyl sulfate actions that promote vascular smooth muscle cell proliferation and migration. Am J Physiol Cell Physiol 2009; 297 (02) C389-C396
    CrossrefPubMedGoogle Scholar
  • 66 Pawlak K, Kowalewska A, Mysliwiec M, Pawlak D. Kynurenine and its metabolites--kynurenic acid and anthranilic acid are associated with soluble endothelial adhesion molecules and oxidative status in patients with chronic kidney disease. Am J Med Sci 2009; 338 (04) 293-300
    CrossrefPubMedGoogle Scholar
  • 67 Moffett JR, Namboodiri MA. Tryptophan and the immune response. Immunol Cell Biol 2003; 81 (04) 247-265
    CrossrefPubMedGoogle Scholar
  • 68 Niinisalo P, Raitala A, Pertovaara M. , et al. Indoleamine 2,3-dioxygenase activity associates with cardiovascular risk factors: the Health 2000 study. Scand J Clin Lab Invest 2008; 68 (08) 767-770
    CrossrefPubMedGoogle Scholar
  • 69 Ozkan Y, Sukuroglu MK, Tulmac M, Kisa U, Simsek B. Relation of kynurenine/tryptophan with immune and inflammatory markers in coronary artery disease. Clin Lab 2014; 60 (03) 391-396
    PubMedGoogle Scholar
  • 70 Kato A, Suzuki Y, Suda T. , et al. Relationship between an increased serum kynurenine/tryptophan ratio and atherosclerotic parameters in hemodialysis patients. Hemodial Int 2010; 14 (04) 418-424
    CrossrefPubMedGoogle Scholar
  • 71 Schefold JC, Zeden JP, Fotopoulou C. , et al. Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: a possible link between chronic inflammation and uraemic symptoms. Nephrol Dial Transplant 2009; 24 (06) 1901-1908
    CrossrefPubMedGoogle Scholar
  • 72 Pawlak K, Domaniewski T, Mysliwiec M, Pawlak D. The kynurenines are associated with oxidative stress, inflammation and the prevalence of cardiovascular disease in patients with end-stage renal disease. Atherosclerosis 2009; 204 (01) 309-314
    CrossrefPubMedGoogle Scholar
  • 73 Eussen SJ, Ueland PM, Vollset SE. , et al. Kynurenines as predictors of acute coronary events in the Hordaland Health Study. Int J Cardiol 2015; 189: 18-24
    CrossrefPubMedGoogle Scholar
  • 74 Chen J, Ren J, Loo WTY, Hao L, Wang M. Lysyl oxidases expression and histopathological changes of the diabetic rat nephron. Mol Med Rep 2018; 17 (02) 2431-2441
    PubMedGoogle Scholar
  • 75 Stangenberg S, Saad S, Schilter HC. , et al. Lysyl oxidase-like 2 inhibition ameliorates glomerulosclerosis and albuminuria in diabetic nephropathy. Sci Rep 2018; 8 (01) 9423-9432
    CrossrefPubMedGoogle Scholar
  • 76 Bhattacharyya S, Wei J, Varga J. Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol 2011; 8 (01) 42-54
    PubMedGoogle Scholar
  • 77 Elhai M, Meune C, Boubaya M. , et al; EUSTAR group. Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis 2017; 76 (11) 1897-1905
    CrossrefPubMedGoogle Scholar
  • 78 Tyndall AJ, Bannert B, Vonk M. , et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 2010; 69 (10) 1809-1815
    CrossrefPubMedGoogle Scholar
  • 79 Hesselvig JH, Kofoed K, Wu JJ, Dreyer L, Gislason G, Ahlehoff O. Localized scleroderma, systemic sclerosis and cardiovascular risk: A Danish Nationwide Cohort Study. Acta Derm Venereol 2018; 98 (03) 361-365
    PubMedGoogle Scholar
  • 80 Łukasik ZM, Makowski M, Makowska JS. From blood coagulation to innate and adaptive immunity: the role of platelets in the physiology and pathology of autoimmune disorders. Rheumatol Int 2018; 38 (06) 959-974
    CrossrefPubMedGoogle Scholar
  • 81 Ramirez GA, Franchini S, Rovere-Querini P, Sabbadini MG, Manfredi AA, Maugeri N. The role of platelets in the pathogenesis of systemic sclerosis. Front Immunol 2012; 3: 160
    PubMedGoogle Scholar
  • 82 Chiang TM, Takayama H, Postlethwaite AE. Increase in platelet non-integrin type I collagen receptor in patients with systemic sclerosis. Thromb Res 2006; 117 (03) 299-306
    CrossrefPubMedGoogle Scholar
  • 83 Chanoki M, Ishii M, Kobayashi H. , et al. Increased expression of lysyl oxidase in skin with scleroderma. Br J Dermatol 1995; 133 (05) 710-715
    PubMedGoogle Scholar
  • 84 Rimar D, Rosner I, Nov Y. , et al. Brief report: lysyl oxidase is a potential biomarker of fibrosis in systemic sclerosis. Arthritis Rheumatol 2014; 66 (03) 726-730
    PubMedGoogle Scholar
  • 85 Rimar D, Rosner I, Slobodin G. , et al. Lysyl oxidase in systemic sclerosis: getting under the skin. Isr Med Assoc J 2016; 18 (09) 534-536
    PubMedGoogle Scholar