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

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. 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...

The Interplay between Non-Esterified Fatty Acids and Plasma Zinc and Its Influence on Thrombotic Risk in Obesity and Type 2 Diabetes

“…HRG is relatively abundant in human plasma ( ca. 1.5 μM), although this value is often elevated in cardiovascular disease [ 92 , 93 ]. HRG is well suited to binding divalent metal ions owing to its histidine-rich region, which possesses 10 binding sites for Zn 2+ ( K D = 1.63 × 10 5 ) [ 94 ].…”

Biomarkers and the post-thrombotic syndrome: A systematic review of biomarkers associated with the occurrence of the post-thrombotic syndrome after lower extremity deep venous thrombosis

“…Four studies measured biomarkers in the acute phase (<1 month), 26,[48][49][50] all except one study 50 measured biomarkers in the subacute phase, and three studies measured biomarkers in the late phase. 26,48,49 Most studies measured biomarkers at discrete timepoints, while some studies grouped measurements at various timepoints, although differing in choice of timepoints and reasoning, for example, based on follow-up time between 4 and 7 months 26 or based on anti-coagulant (AC) treatment between 3 and 12 months. [50][51][52] Some studies excluded patients with recurrent DVT, [48][49][50][52][53][54][55][56][57][58][59] others excluded patients of older age 48,[53][54][55] and some only included patients with proximal DVT.…”

“…26,51,56 Some studies, but not all, excluded patients based on medical history of cancer or recent stroke. 26,48,49,[51][52][53][55][56][57][58][59] For statistical analysis, most studies presented data as either median or mean values, and either odds ratio, or relative risk. Some studies analyzed biomarker values as either continuous variables or as cut-off variables (Tables 4-11).…”

“…D-dimer. Data on the association between Fibrin D-dimer and the occurrence of PTS was reported in ten studies from six different cohorts 26,48,[50][51][52][53][54][55]59,60 (Table 4). D-dimer in the acute phase (at baseline).…”

“…Eight studies from five different cohorts analyzed the association between CRP levels and PTS development (Table 5). 26,48,51,[53][54][55][56][57] Two studies presented data in the acute phase. 56,57 At 0 months (when patients were admitted to the emergency department) neither study found a significant association between CRP levels and PTS development.…”