Recombinant C1-Inhibitor

Relan, Anurag; Bakhtiari, Kamran; Amersfoort, Edwin S. Van; Meijers, Joost C. M.; Hack, C. E.

doi:10.2165/11599490-000000000-00000

Cited by 28 publications

(10 citation statements)

References 33 publications

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“…Despite such limitations, plasma D-dimers are regarded as useful laboratory markers for the diagnosis of thrombotic conditions ( 12 ). Our study corroborates other studies, which have suggested that, despite elevated plasma D-dimers at baseline and during attacks, C1-INH-HAE patients are not at increased thrombotic risk ( 24 , 25 , 27 ). This seemingly paradoxical situation, where activation of the contact coagulation (i.e., via Factor XI), kinin pathway, and fibrinolytic systems does not lead to increased thrombosis, is reconciled by the observation that while FXII-driven fibrin formation is important for pathologic thrombus formation, it has no important function in fibrin formation during normal hemostasis ( 32 ).…”

Section: Discussionsupporting

confidence: 92%

“…As recombinant C1INH (Ruconest®, rhC1INH) is the newest on the market, its potential thrombogenic risk was recently investigated by Relan et al ( 27 ). This study demonstrated that although coagulation and fibrinolysis pathways were indeed activated during acute attacks, treatment with rhC1INH had little or no effect on other coagulation markers, suggesting that it does not exert prothrombotic activity in vivo ( 16 , 22 ).…”

Section: Discussionmentioning

confidence: 99%

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

Reshef

Zanichelli

Longhurst

et al. 2015

Allergy

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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

Reshef

Zanichelli

Longhurst

et al. 2015

Allergy

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“…This is similar to other studies [5,7,13,16] with one exception, where the mean kaolin-cephalin clotting time (equivalent to APTT) was in the upper part of the RR for reasons unknown to us [14]. The majority of our patients with HAE-C1-INH type II and AAE-C1-INH had a shortened APTT, but only a few of those with HAE/AAE with a normal C1-INH.…”

Section: Discussionsupporting

confidence: 93%

“…Our results demonstrated an activation of the kallikrein-kinin (contact) and the intrinsic coagulation system in patients with HAE-C1-INH. Similar results were obtained in other studies, including the formation of complexes of C1-INH with target proteases and an increased formation of thrombin-antithrombin (TAT) complexes and prothrombin fragments 1 and 2 [6,7,8,9,10,11,12,13,14,15,16]. …”

Section: Introductionsupporting

confidence: 88%

Shortened Activated Partial Thromboplastin Time May Help in Diagnosing Hereditary and Acquired Angioedema

Bork

Witzke²

2016

Int Arch Allergy Immunol

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Objective: To evaluate whether activated partial thromboplastin time (APTT) could be used in the laboratory diagnosis of hereditary or acquired angioedema (HAE or AAE) with and without C1 inhibitor (C1-INH) deficiency. Methods: In a prospective investigation, APTT and other coagulation parameters were determined in 149 adult patients with various types of angioedema and in 26 healthy participants (HP). Results: Mean APTT was significantly shortened in HAE-C1-INH type I (p < 0.0001) and type II (p = 0.0017) and in AAE-C1-INH (p < 0.0001) compared to the HP. APTT was shortened under the reference range (26-36 s) in 33/45 (73.3%) patients with HAE-C1-INH, 10/15 (66.7%) patients with AAE-C1-INH, 4/27 (14.8%) patients with HAE with normal C1-INH, 1/32 (3.1%) patients with histaminergic angioedema, 4/30 (13.3%) patients with nonhistaminergic angioedema and in 2/26 (7.7%) HP. Thus, a shortened APTT was obtained in 8-9 times more patients with angioedema due to C1-INH deficiency when compared to patients with various forms of angioedema with normal C1-INH and also to HP. Conclusions: A shortened APTT may help to diagnose HAE-C1-INH and AAE-C1-INH when determination of C1-INH is not yet available.

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“…However, clinical studies with rhC1-INH have not suggested an increased risk of thromboembolic complications [ 36 – 40 ]. Post hoc analyses of the effects of rhC1-INH on coagulation and fibrinolysis in patients with HAE who participated in the randomized, placebo-controlled North American study further supported that rhC1-INH treatment had no prothrombotic effects in patients with HAE receiving up to 100 U/kg [ 36 , 51 ].…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

Recombinant Human C1 Esterase Inhibitor in the Management of Hereditary Angioedema

Riedl

2015

Clin Drug Investig

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Hereditary angioedema (HAE), a rare autosomal dominant genetic disorder, is caused by a deficiency in functional C1 esterase inhibitor (C1-INH). This potentially life-threatening condition manifests as recurrent attacks of subcutaneous and submucosal swelling of the skin, gastrointestinal tract and larynx. The management of HAE includes treatment of acute episodes, short-term prophylaxis in preparation for exposure to known triggers and long-term prophylaxis to decrease the incidence and severity of HAE attacks. Four products are approved in the USA for the treatment of acute attacks of HAE, including one human plasma-derived C1-INH therapy, a recombinant human C1-INH product (rhC1-INH), a plasma kallikrein inhibitor and a bradykinin B2 receptor antagonist. In addition, one human plasma-derived C1-INH therapy and danazol are approved for prophylaxis of HAE attacks. rhC1-INH, extracted from the milk of transgenic rabbits, is a glycoprotein of 478 amino acids with an identical amino acid sequence to the endogenous human C1-INH protein. Population pharmacokinetic analysis of rhC1-INH supports an intravenous dosing strategy of 50 U/kg (maximum 4200 U). The safety and efficacy of rhC1-INH in the treatment of acute attacks in patients with HAE were demonstrated in three randomized, double-blind, placebo-controlled studies and two open-label extension studies. In a pilot prophylaxis study, weekly administration of rhC1-INH 50 U/kg for 8 weeks reduced the incidence of HAE attacks and was well tolerated. Administration of rhC1-INH has not been associated with the development of anti-drug antibodies or antibodies to anti-host-related impurities.

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Recombinant C1-Inhibitor

Cited by 28 publications

References 33 publications

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

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

Shortened Activated Partial Thromboplastin Time May Help in Diagnosing Hereditary and Acquired Angioedema

Recombinant Human C1 Esterase Inhibitor in the Management of Hereditary Angioedema

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