Altered Hypercoagulability Factors in Patients with Chronic Chagas Disease: Potential Biomarkers of Therapeutic Response

Abstract

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.

Target product profile for a test for the early assessment of treatment efficacy in Chagas disease patients: An expert consensus

“…This TPP should guide the development of tests to rapidly evaluate Chagas disease antiparasitic treatment efficacy. These tests might be based on biomarkers derived from the parasite, such as PFR2, KMP11, HSP70, the peptide 3973, F29, αGal-containing antigens, and the list of epitope-based antigens provided by Granjon and colleagues [28][29][30][31][32][33][34]; biomarkers derived from the host, such as hypercoagulability markers F1+2 and ETP [35], and the APOA1 and FN fragments [36]; or a combination of both. At present, preliminary results using Infinity antigen 3 (AG 3; derived from the parasite) and the SaMi-Trop cohort from Brazil show promise, but further insight is required to ensure that the 40% parasite clearance reported upon treatment persists over time [28].…”

Chagas Disease Treatment Efficacy Biomarkers: Myths and Realities

“…F2/3 and A&T antigens obtained from parasites seem to be candidate surrogate biomarkers, but their use in adult studies needs to be further evaluated since the reduction in titers and seroreversion can take longer. Pinazo et al have shown that A&T CL-ELISA remains positive for 3 years after treatment in an adult population [36].…”

“…These markers are elevated in the early stage of the chronic phase and decrease after therapy with BZN [52]. In a more recent study with 99 individuals, Pinazo et al observed that F 1 + 2 and ETP were abnormally expressed in 77% and 50% of infected patients before treatment but returned to, and remained at, normal levels 6-9 months after treatment in 76% and 96% of cases, respectively [36]. This data suggests these markers could assess short-term response to treatment; however, normal values can be observed in infected patients, and some patients show qPCR-positive results even when ETP values reach baseline after treatment.…”

The Ly49E Receptor Inhibits the Immune Control of Acute Trypanosoma cruzi Infection

“…Parasite persistence and unbalanced type 1 inflammatory immune response are likely the dominant determinants of Chagas’ cardiomyopathy. Autoantibodies and a hypercoagulability state might also be involved (1–3). …”