Higher citrullinated histone H3 is associated with postthrombotic syndrome: a cohort study

Postthrombotic syndrome (PTS) is a serious complication of deep vein thrombosis (DVT), linked to persistent inflammation and impaired thrombus resolution. Enhanced formation of neutrophil extracellular traps (NETs) is involved in DVT pathogenesis.

We investigated whether increased NET formation, associated with an unfavorable fibrin clot phenotype, predisposes to the development of PTS.

We studied 179 patients with DVT. Three months after diagnosis and initiation of anticoagulant therapy, citrullinated histone H3 (H3cit), thrombin generation, clot permeability, clot lysis time, and inflammatory markers were measured. PTS severity was assessed at 12 to 14 months by the Villalta score. During a median 53-month follow-up, we recorded recurrent venous thromboembolism and venous ulcers.

Patients with PTS (n = 43, 24.0%) had 68.8% higher H3cit levels compared with those without PTS (P < .001). In the whole group, H3cit showed a positive association with Villalta scores (R = .596; P < .001). Higher H3cit was linked to denser fibrin clots (ie, clot permeability; R = -.352; P < .001), slower fibrinolysis (ie, clot lysis time; R = .287; P < .001), and higher interleukin 6 (R = .429; P < .001), but not C-reactive protein or thrombin generation. In multivariable analysis, higher H3cit per 1 ng/mL at 3 months was independently associated with PTS (odds ratio, 5.50; 95% CI, 2.52-12.01). Patients with recurrent venous thromboembolism (n = 43, 24.0%) had 37.8% higher H3cit concentrations compared with those without recurrence (P < .001). Venous ulcer formation was not related to this marker.

This study is the first to show that enhanced NET formation following DVT may contribute to PTS and its severe forms, at least in part through unfavorable fibrin clot properties.