Elevated D‐dimers in attacks of hereditary angioedema are not associated with increased thrombotic risk

Abstract

BackgroundRecommended management of attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) includes therapy with exogenous C1INH. Thrombotic/thromboembolic events (TEE) have been reported with plasma-derived C1INH, but so far none with recombinant human C1INH (rhC1INH). This phase III, randomized, placebo (saline)-controlled study evaluated the safety of rhC1INH 50 IU/kg for the treatment of acute attacks in 74 patients with C1-INH-HAE.MethodsMonitoring for TEE and assessment of risk of deep vein thrombosis (DVT) by the Wells prediction rule were performed, and levels of fibrin degradation products (plasma D-dimers) were assessed before study drug administration (baseline), 2 h, and 7 days posttreatment.ResultsPlasma D-dimer levels were elevated in 80% of the patients (median [25th–75th percentiles]: 2149 [480–5105] μg/l; normal ≤250 μg/l) and were higher in patients with submucosal (abdominal, oropharyngeal–laryngeal) attacks (3095 [890–10000] μg/l; n = 29) compared with subcutaneous (peripheral, facial) attacks (960 [450–4060] μg/l; n = 35). Median plasma D-dimer levels were comparable across treatment groups at baseline (1874 [475–4568] μg/l rhC1INH; 2259 [586–7533] μg/l saline) and 2 h postinfusion (2389 [760–4974] μg/l rhC1INH; 2550 [310–8410] μg/l saline); median plasma D-dimer levels were decreased by Day 7 in both groups (425 [232–3240] μg/l rhC1INH; 418 [246–2318] μg/l saline). No increased risk of DVT was identified, nor any TEE reported in rhC1INH treated or controls.ConclusionElevated plasma D-dimer levels were associated with acute C1-INH-HAE attacks, particularly with submucosal involvement. However, rhC1INH therapy was not associated with thrombotic events.

Cross Talk Pathways Between Coagulation and Inflammation

“…During episodes, bradykinin levels are elevated and thus increase vascular permeability. In spite of elevated factor XIIa levels and increased D-dimers during acute episodes, 189 hereditary angioedema is not associated with a heightened risk of thrombosis. This is likely related to preferential activation of the vasculoprotective kallikrein-kininogen pathway, evidenced by the increased bradykinin levels and resultant increased generation of PGI 2 , nitric oxide, and plasmin, with reduced TF expression.…”

Hereditary and Acquired Angioedema: Heterogeneity of Pathogenesis and Clinical Phenotypes

“…Recently, Bork and Witzke [48] showed that a shortened activated partial thromboplastin time (aPTT) may help to diagnose C1-INH-HAE and C1-INH-AAE when other tests are not available. aPTT is a routine and easy screening test for the "intrinsic" and "common" pathways of blood coagulation [49].…”

Recombinant Replacement Therapy for Hereditary Angioedema Due to C1 Inhibitor Deficiency

“…These findings were corroborated by Reshef et al who evaluated D-dimer levels, which are consider biomarkers of thrombosis [81]. They reported that treatment with Ruconest did not affect D-dimer levels and was not associated with thrombotic events [82]. Use of any therapeutic protein may lead to the development of antibodies against the protein itself, its plasma counterpart or host-related impurities (HRI).…”