Thromboembolic events were described in patients with Chagas disease without cardiomyopathy. We aim to confirm if there is a hypercoagulable state in these patients and to determine if there is an early normalization of hemostasis factors after antiparasitic treatment. Ninety-nine individuals from Chagas disease-endemic areas were classified in two groups: G1, with T.cruzi infection (n = 56); G2, healthy individuals (n = 43). Twenty-four hemostasis factors were measured at baseline. G1 patients treated with benznidazole were followed for 36 months, recording clinical parameters and performance of conventional serology, chemiluminescent enzyme-linked immunosorbent assay (trypomastigote-derived glycosylphosphatidylinositol-anchored mucins), quantitative polymerase chain reaction, and hemostasis tests every 6-month visits. Prothrombin fragment 1+2 (F1+2) and endogenous thrombin potential (ETP) were abnormally expressed in 77% and 50% of infected patients at baseline but returned to and remained at normal levels shortly after treatment in 76% and 96% of cases, respectively. Plasmin-antiplasmin complexes (PAP) were altered before treatment in 32% of G1 patients but normalized in 94% of cases several months after treatment. None of the patients with normal F1+2 values during follow-up had a positive qRT-PCR result, but 3/24 patients (13%) with normal ETP values did. In a percentage of chronic T. cruzi infected patients treated with benznidazole, altered coagulation markers returned into normal levels. F1+2, ETP and PAP could be useful markers for assessing sustained response to benznidazole.
References
[1]
Schmunis GA, Yadon ZE. Chagas disease: a Latin American health problem becoming a world health problem. Acta Trop 2010; 115(1–2): 14–21. doi: 10.1016/j.actatropica.2009.11.003. pmid:19932071
[2]
Gascon J, Bern C, Pinazo MJ. Chagas disease in Spain, the United States and other non-endemic countries. Acta Trop 2010; 115(1–2): 22–27. doi: 10.1016/j.actatropica.2009.07.019. pmid:19646412
[3]
Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013;13(1): 34–45. doi: 10.1038/nri3345. pmid:23222502
[4]
Schuetz P, Christ-Crain M, Morgenthaler NG, Struck J, Bergman A, Müller B. Circulating precursor levels of endothelin-1 and adrenomedullin, two endothelium-derived, counteracting substances, in sepsis. Endothelium 2007; 14(6): 345–351. pmid:18080871 doi: 10.1080/10623320701678326
[5]
Kreutz RP, Tantry US, Bliden KP, Gurbel PA. Inflammatory changes during the 'common cold' are associated with platelet activation and increased reactivity of platelets to agonists. Blood Coagul Fibrinolysis 2007; 18(8): 713–718. pmid:17982310 doi: 10.1097/mbc.0b013e328201c77e
[6]
Monteiro AC, Schmitz V, Svensjo E, Gazzinelli RT, Almeida IC, Todorov A, et al. Cooperative activation of TLR2 and bradykinin B2 receptor is required for induction of type 1 immunity in a mouse model of subcutaneous infection by Trypanosoma cruzi. J Immunol. 2006; 177(9):6325–6335. pmid:17056563 doi: 10.4049/jimmunol.177.9.6325
[7]
Alejandro Salomone O. Chagas cardiomyopathy and thrombosis: the beginning and the end of a dangerous affair. Rev Esp Cardiol 2003; 56(4): 333–334. pmid:12689565
[8]
Carod-Artal FJ, Vargas AP, Horan TA, Nunes LG. Chagasic cardiomyopathy is independently associated with ischemic stroke in Chagas disease. Stroke 2005; 36(5): 965–970. pmid:15845889 doi: 10.1161/01.str.0000163104.92943.50
[9]
Berra HH, Piaggio E, Revelli SS, Luquita A. Blood viscosity changes in experimentally Trypanosoma cruzi-infected rats. Clin Hemorheol Microcirc 2005; 32(3): 175–182. pmid:15851836
[10]
Herrera RN, Diaz de Amaya EI, Perez Aguilar RC, Joo Turoni C, Mara？ón R, Berman SG, et al. Inflammatory and prothrombotic activation with conserved endothelial function in patients with chronic, asymptomatic Chagas disease. Clin Appl Thromb Hemost 2011; 17(5): 502–507. doi: 10.1177/1076029610375814. pmid:20699256
[11]
Herrera RN, Diaz E, Perez Aguilar R, Bianchi J, Berman S, Luciardi HL. Prothrombotic state in early stages of chronic Chagas' disease. Its association with thrombotic risk factors. Arch Cardiol Mex 2005; 75(3): 38–48.
[12]
Pinazo MJ, Tassies D, Mu？oz J, Fisa R, Posada E de J, Monteagudo J, et al. Hypercoagulability biomarkers in Trypanosoma cruzi -infected patients. Thromb Haemost 2011; 106(4): 617–623. doi: 10.1160/TH11-04-0251. pmid:21866301
[13]
Carod-Artal FJ, Vargas AP, Falcao T. Stroke in asymptomatic Trypanosoma cruzi-infected patients. Cerebrovasc Dis 2011; 31(1): 24–28. doi: 10.1159/000320248. pmid:20980750
[14]
Melo LM, Souza GE, Valim LR, Moreira LF, Damico EA, Rocha TR, et al. Study of pro-thrombotic and pro-inflammatory factors in Chagas cardiomyopathy. Arq Bras Cardiol 2010; 95(5):655–662. pmid:21109919 doi: 10.1590/s0066-782x2010005000146
[15]
Higuchi MdeL, De Morais CF, Sambiase NV, Pereira-Barretto AC, Bellotti G, Pileggi F. Histopathological criteria of myocarditis—a study based on normal heart, chagasic heart and dilated cardiomyopathy. Jpn Circ J 1990;54(4):391–400. pmid:2398619 doi: 10.1253/jcj.54.391
[16]
Higuchi ML, Fukasawa S, De Brito T, Parzianello LC, Bellotti G, Ramires JA. Different microcirculatory and interstitial matrix patterns in idiopathic dilated cardiomyopathy andChagas' disease: a three dimensional confocal microscopy study.Heart. 1999 Sep;82(3):279–285. pmid:10455076 doi: 10.1136/hrt.82.3.279
[17]
Carod-Artal FJ, FdST , Vilela Nunes S et al. Thrombophilia is not a predictive factor of stroke in Chagas Disease. Neurology 2004; 62: A240–241.
[18]
Herrera RN, Díaz E, Pérez R, Chaín S, Sant-Yacumo R, Rodríguez E, et al. The prothrombotic state in early stages of chronic Chagas' disease. Rev Esp Cardiol 2003; 56: 377–382. pmid:12689572 doi: 10.1157/13045653
[19]
World Health Organization (WHO). Control of Chagas’ disease; 2002.
[20]
Bern C, Montgomery SP, Herwaldt BL, Rassi A Jr, Marin-Neto JA, Dantas RO, et al. Evaluation and treatment of chagas disease in the United States: a systematic review. Jama 2007; 298(18): 2171–2181. pmid:18000201 doi: 10.1001/jama.298.18.2171
[21]
Urbina JA. Specific treatment of Chagas disease: current status and new developments. Curr Opin Infect Dis 2001;14(6):733–41. pmid:11964893 doi: 10.1097/00001432-200112000-00012
[22]
Sosa Estani S., Armenti A., Araujo G., Viotti R., Lococo B., Ruiz Vera B., et al. Treatment of Chagas’disease with benznidazole and thioctic acid. Medicina (B. Aires) 2004; 64:1–6.
[23]
Marin-Neto JA, Rassi A Jr., Morillo CA, Avezum A, Connolly SJ, Sosa-Estani S, et al. Rationale and design of a randomized placebo-controlled trial assessing the effects of etiologic treatment in Chagas' cardiomyopathy: the BENznidazole Evaluation For Interrupting Trypanosomiasis (BENEFIT). Am Heart J 2008; 156(1): 37–43. doi: 10.1016/j.ahj.2008.04.001. pmid:18585495
[24]
Rodriques Coura J, de Castro SL. A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz 2002; 97(1): 3–24. pmid:11992141 doi: 10.1590/s0074-02762002000100001
[25]
Viotti R, Vigliano C, Lococo B, Bertochi G, Petti M, álvarez MG, et al. Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial. Ann Intern Med 2006; 144(10): 724–734. pmid:16702588 doi: 10.7326/0003-4819-144-10-200605160-00006
[26]
Requena-Mendez A, Lopez MC, Angheben A, Izquierdo L, Ribeiro I, Pinazo MJ, et al. Evaluating Chagas disease progression and cure through blood-derived biomarkers: a systematic review. Expert Rev Anti Infect Ther 2013; 11(9): 957–976. doi: 10.1586/14787210.2013.824718. pmid:24053276
[27]
Almeida IC, Covas DT, Soussumi LM, Travassos LR. A highly sensitive and specific chemiluminescent enzyme-linked immunosorbent assay for diagnosis of active Trypanosoma cruzi infection. Transfusion 1997; 37(8): 850–857. pmid:9280332 doi: 10.1046/j.1537-2995.1997.37897424410.x
[28]
de Andrade AL, Zicker F, de Oliveira RM, Almeida Silva S, Luquetti A, Travassos LR. Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet 1996; 348(9039): 1407–1413. pmid:8937280 doi: 10.1016/s0140-6736(96)04128-1
[29]
Krettli AU. The utility of anti-trypomastigote lytic antibodies for determining cure of Trypanosoma cruzi infections in treated patients: an overview and perspectives. Mem Inst Oswaldo Cruz 2009; 104 (1): 142–151. doi: 10.1590/s0074-02762009000900020
[30]
Piron M, Fisa R, Casamitjana N, López-Chejade P, Puig L, Vergés M, et al. Development of a real-time PCR assay for Trypanosoma cruzi detection in blood samples. Acta Trop 2007; 103(3): 195–200. pmid:17662227 doi: 10.1016/j.actatropica.2007.05.019
[31]
Riera C, Verges M, López-Chejade P, et al. Desarrollo y evaluación de una técnica ELISA con antígeno crudo de Trypanosoma cruzi para el diagnóstico de la enfermedad de Chagas. Enfermedades emergentes 2009; 11: 19–22.
[32]
Ford RP, Esnouf MP, Burgess AI, Sarphie AF. An enzyme linked immunosorbent assay (ELISA) for the measurement of activated factor XII (Hageman factor) in human plasma. J Immunoassay 1996;17:119–131. pmid:8744282 doi: 10.1080/01971529608005783
[33]
Almeida IC, Ferguson MA, Schenkman S, Travassos LR. Lytic anti-alpha-galactosyl antibodies from patients with chronic Chagas' disease recognize novel O-linked oligosaccharides on mucin-like glycosyl-phosphatidylinositol-anchored glycoproteins of Trypanosoma cruzi. Biochem J 1994; 304 (3): 793–802. doi: 10.1042/bj3040793
[34]
Andrade AL, Martelli CM, Oliveira RM, Silva SA, Aires AI, Soussumi LM, et al. Short report: benznidazole efficacy among Trypanosoma cruzi-infected adolescents after a six-year follow-up. Am J Trop Med Hyg 2004; 71(5): 594–597. pmid:15569790
[35]
Izquierdo L, Marques AF, Gállego M, Sanz S, Tebar S, Riera C, et al. Evaluation of a chemiluminescent enzyme-linked immunosorbent assay for the diagnosis of Trypanosoma cruzi infection in a nonendemic setting. Mem Inst Oswaldo Cruz 2013; 108(7):928–931. doi: 10.1590/0074-0276130112. pmid:24271047
[36]
Almeida IC, Krautz GM, Krettli AU, Travassos LR. Glycoconjugates of Trypanosoma cruzi: a 74 kD antigen of trypomastigotes specifically reacts with lytic anti-alpha-galactosyl antibodies from patients with chronic Chagas disease. J Clin Lab Anal 1993; 7(6): 307–316. pmid:8277354 doi: 10.1002/jcla.1860070603
[37]
Greenacre MJ. Theory and Applications of Correspondence Analysis. London: Academic Press.1984.
[38]
Greenacre MJ, Blasius J. From simple to multiple correspondence analysis. In Multiple Correspondence Analysis and Related Methods, ed. Raton Boca, 2006. FL: Chapman & Hall/CRC.
[39]
Manucci PM. Mechanisms, markers and management of coagulation activation. Thrombosis 1993; 44: 851–870.
[40]
Schaller J, Gerber SS. The plasmin-antiplasmin system: structural and functional aspects. Cell Mol Life Sci 2011; 68(5): 785–801. doi: 10.1007/s00018-010-0566-5. pmid:21136135
[41]
Ferroni P, Martini F, Riondino S, La Farina F, Magnapera A, Ciatti F, et al. Soluble P-selectin as a marker of in vivo platelet activation. Clin Chim Acta 2009; 399(1–2): 88–91. doi: 10.1016/j.cca.2008.09.018. pmid:18835553
