Increased levels of histidine-rich glycoprotein are associated with the development of post-thrombotic syndrome

Krzysztof Plens,Joanna Natorska,Anetta Undas,Jakub Siudut,Maksim Son

doi:10.1038/s41598-020-71437-5

Abstract

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.

Highlights

Denser fibrin networks which are relatively resistant to lysis can predispose to post-thrombotic syndrome (PTS)
Analysis of fibrin clot properties showed that baseline Histidine-rich glycoprotein (HRG) levels correlated with plasma clot permeability (r = − 0.41, p < 0.001), maximum absorbance (r = 0.24, p = 0.002), and two fibrinolysis measures, i.e. clot lysis time (r = 0.41, p < 0.001) and maximum rate of increase in D-dimer levels released from clots (r = − 0.16, p = 0.04; Fig. 2)
Variable Age, years Male n, (%) BMI, kg/m2 Blood type, n (%) A B 0 AB Clinical characteristics, n (%) Smoking Trauma/surgery Unprovoked venous thromboembolism (VTE) deep-vein thrombosis (DVT) with PE Family history of VTE Proximal DVT Baseline laboratory parameters international normalized ratio (INR) D-dimer, ng/mL Fibrinogen, g/L Creatinine, μmol/L Glucose, mmol/L TC, mmol/L TG, mmol/L CRP, mg/L IL-6, pg/mL IL-10, pg/mL HRG, μg/mL Factor VIII, % type plasminogen activator (tPA) Ag, ng/mL plasminogen activator inhibitor-1 (PAI-1) Ag, ng/mL thrombin-activatable fibrinolysis inhibitor (TAFI) activity, μg/mL Plasminogen, % α-antiplasmin, % Peak thrombin, nM Fibrin clot formation and features Plasma clot permeability, 10−9cm[2] Clot lysis time, min Lag time, sec Maximum absorbance Maximum levels of D‐dimer released from clots, mg/L Maximum rate of increase in D-dimer levels released from clots, mg/L/min Genetic polymorphisms, n (%) Factor V Leiden Prothrombin 20210A Factor XIII Val34Leu α-fibrinogen Thr312Ala

Summary

Introduction

Denser fibrin networks which are relatively resistant to lysis can predispose to post-thrombotic syndrome (PTS). Post-thrombotic syndrome (PTS) affects as many as 23–60% of patients in the first 2 years of deep-vein thrombosis (DVT)[1]. 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]. 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 P TS11.

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Conclusion