C1 inhibitor deficiency linked to greater activation of coagulation, enhanced VTE
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Endogenous C1 esterase inhibitor is an important negative regulator of coagulation, according to study results presented at ASH Annual Meeting and Exposition.
Hereditary angioedema is associated with enhanced contact pathway-mediated coagulation and an increased risk for venous thromboembolism, findings presented during the meeting’s plenary session showed.
“Further, [C1 esterase inhibitor (C1INH)]-deficient mice model key aspects of the procoagulant phenotype associated with [hereditary angioedema] and we’re working to elucidate the mechanisms,” Steven P. Grover, PhD, postdoctoral fellow at UNC Blood Research Center, said during a presentation.
Background
C1INH — a large multifunctional serine protease inhibitor encoded by the SERPING1 gene — is a negative regular of the contact pathway.
It is expressed primarily in the liver, and it has a circulating plasma concentration of approximately 0.2 mg/ml, according to study background.
Targets include components of the contact, complement and fibrinolytic systems.
Congenital C1INH deficiency causes hereditary angioedema, an autosomal dominant disease primarily caused by mutations in the SERPING1 gene. The condition causes reduced plasma C1INH levels or impaired C1INH function.
The rare condition — which affects approximately one in 50,000 individuals — presents with episodes of subcutaneous or submucosal swelling.
“Swelling is driven primarily by bradykinin-mediated enhancement of vascular permeability and, interestingly, there is evidence of coagulation abnormalities in these patients,” Grover said.
These abnormalities include elevated plasma levels of markers and coagulation, including prothrombin fragments, thrombin-antithrombin complexes and D-dimer. Clinical coagulation assays also show activated partial thromboplastin time.
“Despite this procoagulant state, [hereditary angioedema] is not classically associated with thrombotic pathologies,” Grover said.
Methodology
Grover and colleagues hypothesized that C1INH deficiency enhances contact pathway-mediated activation of coagulation and thrombosis.
Researchers used epidemiologic studies, clinical samples and mouse models to test this hypothesis.
Investigators gained access to a registry from Sweden that included 239 patients with hereditary angioedema, as well as 2,383 age- and sex-matched healthy controls.
Researchers used ICD-10 codes to extract information about venous thromboembolism — including deep vein thrombosis, pulmonary embolism and other VTE — and arterial thromboembolism, including ischemic heart disease and cerebral infarction.
Results
Results showed no statistically significant association between hereditary angioedema and DVT (OR = 2.24; 95% CI, 0.81-6.42) or VTE (OR = 1.91; 95% CI, 0.7-5.25); however, researchers observed a significant association between hereditary angioedema and composite VTE (OR = 3.59; 95% CI, 2.17-5.84).
Results showed no statistically significant association between hereditary angioedema and ischemic heart disease (OR = 1.23; 95% CI, 0.65-2.24), cerebral infarction (OR = 0.76; 95% CI, 0.29-2.05) or a composite arterial thromboembolism (OR = 1.3; 95% CI, 0.81-2.09).
Grover and colleagues performed further investigation using clinical 39 samples obtained from collaborators in Hungary. Nineteen samples came from patients with hereditary angioedema (moderate C1INH deficiency, n = 9; severe C1INH deficiency, n = 10) and 20 came from age- and sex-matched controls.
Researchers calculated thrombin generation by calibrated automated thrombography.
Analysis of thrombin generation triggered by the contact pathway agonist silica showed an apparent increase in thrombin generation among samples from patients with hereditary angioedema. Quantification analysis showed a significant shortening of thrombin generation lag time among patients with sever C1INH deficiency and a significant increase in peak thrombin generation in that same population.
Researchers observed no difference in tissue factor-initiated thrombin generation/
“This indicates that severe C1INH deficiency supports a selective enhancement of contact pathway-mediated thrombin generation,” Grover said.
Additional analyses showed C1INH-deficient mice exhibited significantly elevated plasma levels of multiple coagulation markers — including prothrombin fragment 1+2, thrombin-antithrombin complexes and D-dimer — at baseline compared with wild-type littermate controls.
C1INH-deficient mice also exhibited enhanced venous thrombus formation in the inferior vena cava stenosis model of venous thrombosis, as shown by elevated thrombus weight.
Loss of C1INH demonstrated no effect on venous thrombus composition, results showed.
Arterial thrombus formation in the carotid artery ferric chloride model of arterial thrombosis did not differ significantly between C1INH-deficient mice and wild-type controls, nor did hemostasis as assessed using a tail transection model.
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Grover SP, et al. Abstract 5. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
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