Contact system activation and high thrombin generation in hyperthyroidism

Background

Hyperthyroidism is associated with increased thrombotic risk. As contact system activation through formation of neutrophil extracellular traps (NET) has emerged as an important trigger of thrombosis, we hypothesized that the contact system is activated along with active NET formation in hyperthyroidism and that their markers correlate with disease severity.

Subjects and methods

In 61 patients with hyperthyroidism and 40 normal controls, the levels of coagulation factors (fibrinogen, and factor VII, VIII, IX, XI and XII), D-dimer, thrombin generation assay (TGA) markers, NET formation markers (histone–DNA complex, double-stranded DNA and neutrophil elastase) and contact system markers (activated factor XII (XIIa), high-molecular-weight kininogen (HMWK), prekallikrein and bradykinin) were measured.

Results

Patients with hyperthyroidism showed higher levels of fibrinogen (median (interquartile range), 315 (280–344) vs 262 (223–300), P = 0.001), D-dimer (103.8 (64.8–151.5) vs 50.7 (37.4–76.0), P < 0.001), peak thrombin (131.9 (102.2–159.4) vs 31.6 (14.8–83.7), P < 0.001) and endogenous thrombin potential (649 (538–736) vs 367 (197–1147), P = 0.021) in TGA with 1 pM tissue factor, neutrophil elastase (1.10 (0.39–2.18) vs 0.23 (0.20–0.35), P < 0.001), factor XIIa (66.9 (52.8–87.0) vs 73.0 (57.1–86.6), P < 0.001), HMWK (6.11 (4.95–7.98) vs 3.83 (2.60–5.68), P < 0.001), prekallikrein (2.15 (1.00–6.36) vs 1.41 (0.63–2.22), P = 0.026) and bradykinin (152.4 (137.6–180.4) vs 118.3 (97.1–137.9), P < 0.001) than did normal controls. In age- and sex-adjusted logistic regression analysis, fibrinogen, factor VIII, IX and XIIa, D-dimer, peak thrombin, neutrophil elastase, HMWK and bradykinin showed significant odds ratios representing hyperthyroidism’s contribution to coagulation and contact system activation. Free T4 was significantly correlated with factors VIII and IX, D-dimer, double-stranded DNA and bradykinin.

Conclusion

This study demonstrated that contact system activation and abundant NET formation occurred in the high thrombin generation state in hyperthyroidism and were correlated with free T4 level.

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