Management of severe congenital protein C deficiency with a direct oral anticoagulant, edoxaban: A case report

Watanabe, Kentaro; Arakawa, Yuki; Yanagi, Masato; Isobe, Koichi; Mori, Makiko; Koh, Katsuyoshi

doi:10.1002/pbc.27686

Cited by 12 publications

(9 citation statements)

References 15 publications

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“…Cisneros GS et al published a case report of a 17-year-old male patient with severe PC deficiency that was successfully managed with the use of a direct oral Xa inhibitor, rivaroxaban [32]. Another direct oral anticoagulant, edoxaban, may be the more favorable treatment option for patients with severe PC deficiency because it can be administered as a simple suspension and has fewer drug interactions [38]. Therefore, FFP replacement and/or direct oral anticoagulant may be a promising alternative for the management of congenital PC deficiency.…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic features of Chinese pediatric patients with severe congenital protein C deficiency who first presented with purpura fulminans: A case series study and literature review

Tang

Zhang

Yang

et al. 2022

Thrombosis Research

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Introduction: Purpura fulminans (PF) is a hematological emergency that can be caused by severe congenital protein C (PC) deficiency. It has been rarely reported in the Chinese population. We aimed to characterize the clinical and genetic features of Chinese pediatric patients with severe congenital PC deficiency who first presented with PF. Materials and methods: Twelve pediatric patients were diagnosed with severe congenital PC deficiency with PF, which was diagnosed based on our hospital records and previous reports from 1988 to July 2021 in China. We evaluated the clinical and genetic features of these patients. Results: Nine patients (9/12, 75%) had onsets that were observed within the first 48 h after birth. Six patients had a family history of thromboembolism. There was no consanguinity. Other symptoms were intracranial thrombosis or hemorrhage (4, 33.3%), ocular lesions (2, 16.7%), gastrointestinal hemorrhage (2, 16.7%) and kidney infarction before birth (1, 8.3%). All but one of the patients (one case not detected) had a plasma PC activity of <10%. The genetic study indicated that in the eight patients with inherited PC deficiency, two were homozygous, five were compound heterozygous and one was heterozygous for PC deficiency. Conclusion: This is the first and largest case series of Chinese pediatric patients with severe congenital PC deficiency who first presented with PF. It has been shown that treatment with both fresh frozen plasma and anticoagulants is recommended when PC concentrate is not easily available, especially in developing countries.

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Section: Discussionmentioning

confidence: 99%

Clinical and genetic features of Chinese pediatric patients with severe congenital protein C deficiency who first presented with purpura fulminans: A case series study and literature review

Tang

Zhang

Yang

et al. 2022

Thrombosis Research

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“…At the age of 12.5 years, due to more frequent problems with the pump system and the risk of reduced patient compliance, we decided together with the family to start an off-label therapy with apixaban (DOAC) 3 × 5 mg/day. DOACs might control protein C deficiency in a more stable manner than vitamin K antagonists due to more constant drug levels and fewer side effects and because the former suppress the thrombotic tendency without reducing protein C and protein S production ( 27 ). However, little is known about the use of DOACs for pediatric patients and patients with protein C deficiency ( 27 – 29 ).…”

Section: Discussionmentioning

confidence: 99%

“…DOACs might control protein C deficiency in a more stable manner than vitamin K antagonists due to more constant drug levels and fewer side effects and because the former suppress the thrombotic tendency without reducing protein C and protein S production ( 27 ). However, little is known about the use of DOACs for pediatric patients and patients with protein C deficiency ( 27 – 29 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Successful Long-Term Management of a Low-Birth Weight Preterm Infant With Compound Heterozygous Protein C Deficiency With Subcutaneous Protein C Concentrate Up to Adolescence

et al. 2021

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Homozygous/compound heterozygous forms of congenital protein C deficiency are often associated with severe antenatal and postnatal thrombotic or hemorrhagic complications. Protein C deficiency frequently leads to severe adverse outcomes like blindness and neurodevelopmental delay in children and may even lead to death. The most widely used long-term postnatal treatment consists of oral anticoagulation with vitamin K antagonists (e.g., warfarin), which is supplemented with protein C concentrate in acute phases. Subcutaneous infusions have been described in infants mostly from 2 months of age after severe postnatal thrombosis, but not in newborns or premature infants without thromboembolism. We report the first case of a compound heterozygous protein C-deficient preterm infant, born at 31+5 weeks of gestation to parents with heterozygous protein C deficiency (protein C activity 0.9% at birth). We focus on both prenatal and perinatal management including antithrombotic treatment during pregnancy, the cesarean section, and continuous postnatal intravenous and consecutive subcutaneous therapy with protein C concentrate followed by a change of therapy to direct oral anticoagulants (DOACs) (apixaban). We report successful home treatment with subcutaneous protein C concentrate substitution overnight (target protein C activity >25%) without complication up to 12.5 years of age. We propose that early planned cesarean section at 32 or preferably 34 weeks of gestation limits potential maternal side effects of anticoagulation with vitamin K antagonists and reduces fetal thromboembolic complications during late pregnancy. Intravenously administered protein C and early switch to subcutaneous infusions (reaching about 3 kg body weight) resulted in sufficient protein C activity and has guaranteed an excellent quality of life without any history of thrombosis for 13 years now. In older children with protein C deficiency, as in our case, DOACs could be a new therapeutic option.

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“…However, these analyses included patients only with mild PC deficiency. Experience of DOACs or LMWH in severe PC deficiency is restricted to single case reports . The use of selective direct inhibitors of FIIa or FXa in other severe prothrombotic disorders such as antiphospholipid syndrome remains controversial because of incomplete efficacy in some studies …”

Section: Introductionmentioning

confidence: 99%

“…Experience of DOACs or LMWH in severe PC deficiency is restricted to single case reports. [20][21][22][23][24][25] The use of selective direct inhibitors of FIIa or FXa in other severe prothrombotic disorders such as antiphospholipid syndrome remains controversial because of incomplete efficacy in some studies. 15,26 The aim of this study was to evaluate the in-vitro effects of direct FIIa and FXa inhibitors, alongside the indirect dual FXa/FIIa inhibitor enoxaparin in PC-deficient plasma using modified thrombin generation and viscoelastometry assays that were sensitive to PC anticoagulant activity.…”

Section: Introductionmentioning

confidence: 99%

Differential effects of direct factor IIa and factor Xa inhibitors in protein C‐deficient plasma detected using thrombin generation and viscoelastometry assays

Aungraheeta

Reilly‐Stitt

Mumford

2019

Int J Lab Hematology

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Introduction Protein C (PC) deficiency results in dysregulated thrombin generation and increases thrombosis risk. Methods In order to investigate the potential effects of anticoagulant drugs in PC deficiency, we evaluated the pharmacodynamic effect of selective direct factor (F) IIa inhibitors (dabigatran and argatroban), selective direct FXa inhibitors (rivaroxaban and apixaban) and an indirect FXa/FIIa inhibitor (enoxaparin) in commercial PC‐deficient plasma using thrombin generation and viscoelastometry assays modified to reflect PC anticoagulant activity. Results Endogenous thrombin potential (ETP) and peak thrombin concentration (PTC) were increased in PC‐deficient plasma but this corrected completely with PC concentrate. Inhibition of FIIa and FXa with the selective inhibitors also corrected the increased ETP and PTC but required high drug concentrations. There was sustained low‐level thrombin generation in PC‐deficient plasma with FXa inhibitors but not with FIIa inhibitors. Adding PC concentrate to PC‐deficient plasma anticoagulated with dabigatran had little additional effect on ETP or PTC. In contrast, addition of even small quantities of PC concentrate to PC‐deficient plasma anticoagulated with rivaroxaban further diminished ETP, primarily by abolishing sustained thrombin generation. In the viscoelastometry assay, the coagulation time was shortened and α‐angle increased in PC‐deficient plasma. These abnormalities reversed with both dabigatran and rivaroxaban. Conclusion The selective direct FXa and FIIa inhibitors at high concentrations both counteracted the abnormal thrombin generation and clot formation observed in PC‐deficient plasma, but with qualitative differences in their effects.

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Management of severe congenital protein C deficiency with a direct oral anticoagulant, edoxaban: A case report

Cited by 12 publications

References 15 publications

Clinical and genetic features of Chinese pediatric patients with severe congenital protein C deficiency who first presented with purpura fulminans: A case series study and literature review

Clinical and genetic features of Chinese pediatric patients with severe congenital protein C deficiency who first presented with purpura fulminans: A case series study and literature review

Case Report: Successful Long-Term Management of a Low-Birth Weight Preterm Infant With Compound Heterozygous Protein C Deficiency With Subcutaneous Protein C Concentrate Up to Adolescence

Differential effects of direct factor IIa and factor Xa inhibitors in protein C‐deficient plasma detected using thrombin generation and viscoelastometry assays

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