Rivaroxaban dose adjustment using thrombin generation in severe congenital protein C deficiency and warfarin-induced skin necrosis

Menon, Neethu; Sarode, Ravindra; Zia, Ayesha

doi:10.1182/bloodadvances.2017012047

Cited by 17 publications

(20 citation statements)

References 22 publications

(19 reference statements)

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“…Our subgroup analysis in patients with hereditary natural anticoagulant deficiencies showed no statistically significant differences in efficacy or safety between DOACs and VKA, but was limited by the low number of events. For protein C deficiency, the published clinical experience on DOAC use was generally in line with our results, with only 1 treatment failure reported by Boey et al [8,9,43,46,47,50,51]. On the contrary, available anecdotal reports indicate more treatment failures than successes among protein S-deficient patients treated with DOACs [10,47].…”

Section: Discussionsupporting

confidence: 90%

Direct oral anticoagulants in patients with venous thromboembolism and thrombophilia: a systematic review and meta‐analysis

Elsebaie

Langston

et al. 2019

Journal of Thrombosis and Haemostasis

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We investigated direct oral anticoagulant (DOAC) use in venous thromboembolism and thrombophilia. A comprehensive search identified 10 studies, 8 of which were included in a meta‐analysis. DOACs were overall safe and effective in patients with venous thromboembolism and thrombophilia. Efficacy/safety of DOACs was maintained in low‐risk antiphospholipid syndrome patient subgroup. Summary BackgroundDirect oral anticoagulants (DOACs) are increasingly used in acute and long‐term treatment of venous thromboembolism (VTE). However, their role in management of thrombophilia‐associated VTE is controversial. MethodsThrough a comprehensive search on MEDLINE, Cochrane Library, and Clinicaltrials.gov, we identified 10 eligible studies, 8 of which reporting data on 1994 thrombophilia patients were included in a random‐effects meta‐analysis. Eligible studies were phase 2 to 3 randomized controlled trials comparing DOACs to vitamin K antagonists (VKAs) in patients with VTE, including those with thrombophilia. ResultsOf eight studies included in meta‐analysis, four evaluated rivaroxaban, three dabigatran, and one edoxaban. No results could be obtained on apixaban use. The rates of VTE recurrence (RR, 0.70; 95% CI, 0.34–1.44; I2 = 0%) and major/clinically relevant non‐major bleeding events (RR, 0.92; 95% CI, 0.62–1.36; I2 = 23%) were similar between thrombophilia patients treated with DOACs compared to VKAs. Results were comparable to findings in patients without known thrombophilia: RR, 1.02; 95% CI, 0.80–1.30; I2 = 46% for VTE recurrence and RR, 0.72; 95% CI, 0.57–0.90; I2 = 84% for major/clinically relevant non‐major bleeding events. ConclusionsRates of VTE recurrence and bleeding events were both low and comparable in patients with various thrombophilias receiving either treatment, suggesting that DOACs are an appropriate treatment option in this population. Due to limited data, it is unclear whether these findings apply to specific subgroups such as high‐risk antiphospholipid syndrome, uncommon thrombophilias, or the use of apixaban.

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Section: Discussionsupporting

confidence: 90%

Direct oral anticoagulants in patients with venous thromboembolism and thrombophilia: a systematic review and meta‐analysis

Elsebaie

Langston

et al. 2019

Journal of Thrombosis and Haemostasis

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“…One important limitation of this study is that one should be cautious to extrapolate the results of these in‐vitro thrombin generation and viscoelastometry assays using commercial PC‐deficient plasma to the clinical setting of PC deficiency. However, in keeping with anaecdotal clinical observations that high doses of direct‐acting anticoagulants are required to prevent thrombosis, our data suggest that existing licensed dose regimes for treatment of VTE may be insufficient in severe protein C deficiency. Our data also provide preliminary evidence of an additive effect of PC concentrate and rivaroxaban on correcting abnormal thrombin generation in vitro and raises the important possibility of a clinical application of direct FXa inhibitors as adjunctive treatment to reduced intensity PC replacement.…”

Section: Discussionsupporting

confidence: 72%

“…Consistent with this hypothesis, sustained thrombin generation with the direct FXa inhibitor rivaroxaban was prevented by adding even small quantities of PC concentrate.One important limitation of this study is that one should be cautious to extrapolate the results of these in-vitro thrombin generation and viscoelastometry assays using commercial PC-deficient plasma to the clinical setting of PC deficiency. However, in keeping with anaecdotal clinical observations that high doses of direct-acting anticoagulants are required to prevent thrombosis,23 our data suggest that existing licensed dose regimes for treatment of VTE may be insufficient in severe protein C deficiency. Our data also provideF I G U R E 4 Selective FIIa and FXa inhibitors combined with PC replacement in protein C-deficient plasma.…”

supporting

confidence: 77%

“…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%

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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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Thrombin Generation in Trauma Patients: How Do we Navigate Through Scylla and Charybdis?

Mitrophanov

Vandyck

Tanaka

2022

Curr Anesthesiol Rep

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Purpose of Review Coagulopathy is a complex pathological condition manifested through the insufficient or excessive tendency to form blood thrombi, which can be caused by trauma and surgery. A promising strategy to mitigate coagulopathy is the balanced restoration of the generation of thrombin — the main enzyme in the blood-coagulation system. We review studies focusing on thrombin, traumatic coagulopathy, and hemostatic balance — a concept aimed to avoid abnormally weak or excessively strong coagulation responses. Recent Findings Thrombin generation is impacted by coagulopathic conditions described by complex patterns, possibly depending on various factors. New methodologies of thrombin-generation measurement and analysis are emerging. Combinations of pro- and anticoagulant proteins can restore thrombin generation in coagulopathy. Balanced therapeutic strategies to improve thrombin generation may lead to favorable clinical outcomes. Summary Thrombin generation is an essential target of pharmacological intervention in traumatic and surgical coagulopathy. Graphic Abstract

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Rivaroxaban dose adjustment using thrombin generation in severe congenital protein C deficiency and warfarin-induced skin necrosis

Abstract: Key Points Rivaroxaban was efficacious and safe in a child with protein C deficiency to prevent the recurrence of skin necrosis or venous thrombosis. The dosage of direct oral anticoagulants in children with thrombophilia is unclear; a thrombin generation assay may be useful to adjust it.

Cited by 17 publications

References 22 publications

Direct oral anticoagulants in patients with venous thromboembolism and thrombophilia: a systematic review and meta‐analysis

Direct oral anticoagulants in patients with venous thromboembolism and thrombophilia: a systematic review and meta‐analysis

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

Thrombin Generation in Trauma Patients: How Do we Navigate Through Scylla and Charybdis?

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