High Levels of Complement Activating Enzyme MASP-2 Are Associated With the Risk of Future Incident Venous Thromboembolism

Abstract

BACKGROUND: Experimental studies have shown that the complement activating enzyme MASP-2 (mannose-binding lectin associated serine protease 2) exhibits a thrombin-like activity and that inhibition of MASP-2 protects against thrombosis. In this study, we investigated whether plasma MASP-2 levels were associated with risk of future venous thromboembolism (VTE) and whether genetic variants linked to MASP-2 levels were associated with VTE risk. METHODS: We conducted a population-based nested case-control study involving 410 VTE patients and 842 age- and sex-matched controls derived from the Norwegian Tromsø Study. Logistic regression was used to estimate odds ratios (ORs) of VTE across MASP-2 quartiles. Whole-exome sequencing and protein quantitative trait loci analyses were performed to assess genetic variants associated with MASP-2 levels. A 2-sample Mendelian randomization study, also including data from the INVENT consortium (International Network of Venous Thrombosis), was performed to assess causality. RESULTS: Subjects with plasma MASP-2 in the highest quartile had a 48% higher OR of VTE (OR, 1.48 [95% CI, 1.06–2.06]) and 83% higher OR of deep vein thrombosis (OR, 1.83 [95% CI, 1.23–2.73]) compared with those with MASP-2 levels in the lowest quartile. The protein quantitative trait loci analysis revealed that 3 previously described gene variants, rs12711521 (minor allele frequency, 0.153), rs72550870 (minor allele frequency, 0.045; missense variants in the MASP2 gene), and rs2275527 (minor allele frequency, 0.220; exon variant in the adjacent MTOR gene) explained 39% of the variation of MASP-2 plasma concentration. The OR of VTE per 1 SD increase in genetically predicted MASP-2 was 1.03 ([95% CI, 1.01–1.05] P =0.0011). CONCLUSIONS: Our findings suggest that high plasma MASP-2 levels are causally associated with risk of future VTE.

Fibrinogen Cleavage by Lectin Pathway Proteases: Roles and Implications

“…Genomic and proteomic dysregulation of lectin proteases exacerbate the disease consequences as upregulation of MASP-1, 2, and 3 eventually increases the embolism possibility [78,79]. Upregulation of lectin pathway-associated proteins predisposes towards autoimmune disease susceptibility such as Hashimoto's thyroiditis [80] and Systemic Lupus Erythematosus (SLE) [26].…”

Recent Advances on the Molecular Mechanism and Clinical Trials of Venous Thromboembolism

“…[70][71][72][73][74] According to the study by Damoah et al, having elevated levels of the complement-activating enzyme Masp-2 raises the chance for developing venous thromboembolism in the future. 75 Furthermore, the absence of B cells in mice indirectly contributes to venous thrombosis by elevating neutrophil counts and increasing fibrinogen levels. The inferior vena cava (IVC) stenosis model demonstrated an augmented incidence of venous thrombosis due to B-cell deficiency, which was hypothesized by investigators to be caused by a rise in circulating neutrophils leading to an increased abundance of NETs within the thrombus and upregulation of fibrinogen production.…”

Hereditary angioedema is associated with an increased risk of venous thromboembolism

“…15 Epidemiological studies have found high plasma levels of complement factors MASP2, C3, and C5 to be associated with an increased risk of VTE. [16][17][18] Importantly, patients with HAE typically have low plasma levels of functional complement factor C4, likely caused by aberrant activation of the complement system and consumption of this factor. 19 The advent of C1INH replacement therapies, including purified plasma C1INH and recombinant C1INH preparations, represented an important advance in the treatment of patients with HAE.…”