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Denser fibrin networks which are relatively resistant to lysis can predispose to post-thrombotic syndrome (PTS). Histidine-rich glycoprotein (HRG), a blood protein displaying antifibrinolytic properties, is present in fibrin clots. We investigated whether HRG may affect the risk of PTS in relation to alterations to fibrin characteristics. In venous thromboembolism (VTE) patients, we evaluated plasma HRG levels, plasma clot permeability, maximum absorbance, clot lysis time and maximum rate of increase in D-dimer levels released from clots after 3 months of the index event. We excluded patients with cancer and severe comorbidities. After 2 years of follow-up, 48 patients who developed PTS had 18.6% higher HRG at baseline. Baseline HRG positively correlated with clot lysis time, maximum absorbance, and thrombin-activatable fibrinolysis inhibitor (TAFI) activity but was inversely correlated with plasma clot permeability and maximum rate of increase in D-dimer levels released from clots. On multivariate regression model adjusted for age, fibrinogen and glucose, independent predictors of PTS were recurrent VTE, baseline HRG level, and TAFI activity. VTE recurred in 45 patients, including 30 patients with PTS, and this event showed no association with elevated HRG. Our findings suggest that increased HRG levels might contribute to the development of PTS, in part through prothrombotic fibrin clot properties. Post-thrombotic syndrome (PTS) affects as many as 23-60% of patients in the first 2 years of deep-vein thrombosis (DVT) 1. It is a constellation of signs and symptoms of chronic deep venous insufficiency and typically manifests as swelling, pain, peripheral oedema, venous ectasia, and in advanced cases-ulceration. The severity is usually determined using the Villalta scale 2. PTS is thought to arise from chronic thrombotic obstruction of the deep veins leading to venous hypertension, exacerbated by valvular incompetence 3. Residual vein obstruction post DVT has been reported to be linked to impaired fibrinolysis and disturbed microcirculation 4-7. The exact mechanism underlying PTS is poorly understood. PTS results at least in part from delayed venous thrombus resolution and induction of vein wall fibrosis, which promotes valvular reflux 8. Robust evidence indicates that PTS is closely associated with enhanced systemic inflammation 3. Fibrin formation is the final stage of blood coagulation. Fibrin clot structure is highly heterogeneous and determined by several genetic and environmental factors, with a commonly observed prothrombotic phenotype involving the formation of denser fibrin networks which are relatively resistant to lysis 9. Such altered fibrin clot properties have been observed in unprovoked venous thromboembolism (VTE) 9. The prothrombotic clot phenotype has also been reported to increase risk of recurrent DVT 10. In 2016 Siudut et al. found that lowered fibrin clot permeability and impaired lysis assessed off anticoagulation following a few months since the first DVT predispose patients to develop PTS 1...

Background and Purpose— We hypothesized that formation of left atrial appendage (LAA) thrombi of unknown origin is associated with altered fibrin clot properties and blood hypercoagulability. Methods— In a case–control study, we investigated 32 patients with a history of LAA thrombus after successful anticoagulant treatment versus 32 control subjects matched for age, sex, and diabetes mellitus. All subjects had previous ischemic stroke, transient ischemic attack, or migraine associated with patent foramen ovale. Patients with documented atrial fibrillation were excluded. We determined plasma fibrin clot permeability, fibrinolytic efficiency, thrombin generation, platelet and endothelial markers. Stroke or transient ischemic attack were assessed during a median follow-up of 74 (range 19–98) months. Results— Compared with controls, patients with LAA thrombus more frequently were smokers (43.8% versus 18.8%) and had 20% prolonged clot lysis time, lower plasminogen (−14%), and higher plasminogen activator inhibitor-1 (+17%), thrombin–antithrombin complexes (+17%), CD40 ligand (+30%), P-selectin (+29%), and von Willebrand factor (+30%, all P <0.05). Occurrence of LAA thrombus was predicted by von Willebrand factor (β=0.038, P =0.004), plasminogen (β=−0.048, P =0.01), plasminogen activator inhibitor-1 (β=−0.161, P =0.03), and clot permeability (β=−1.076, P =0.03). During follow-up, cerebrovascular events occurred in 10 (33.33%) of the 30 available patients in the LAA thrombus group, including 7 (23.3%) with recurrent LAA thrombus and 4 (13.33%) with documented atrial fibrillation. Recurrent LAA thrombus was associated with lower baseline K s and higher thrombin generation, fibrinogen, plasminogen activator inhibitor-1, and soluble CD40 ligand (all P <0.05). Conclusions— Prothrombotic blood alterations could be involved in the LAA thrombus formation in patients without documented atrial fibrillation and are associated with increased risk of stroke or transient ischemic attack during follow-up.