Novel protein C gene mutation in a compound heterozygote resulting in catastrophic thrombosis in early adulthood: diagnosis and long‐term treatment with subcutaneous protein C concentrate

Boey, Jir Ping; Jolley, Alexandra; Nicholls, Catherine; Lerda, Nancy; Duncan, Elizabeth M.; Gallus, Alexander; Ross, David M.; Sobieraj‐Teague, Magdalena

doi:10.1111/bjh.13538

Cited by 16 publications

(18 citation statements)

References 11 publications

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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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“…64,65 Catastrophic venous thrombosis in a young adult with protein C deficiency has also been reported. 66 Management includes replacement of the deficient natural anticoagulant with fresh-frozen plasma or protein C concentrates.…”

Section: Other Disordersmentioning

confidence: 99%

How I treat catastrophic thrombotic syndromes

Ortel

Erkan

Kitchens

2015

Blood

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Catastrophic thrombotic syndromes are characterized by rapid onset of multiple thromboembolic occlusions affecting diverse vascular beds. Patients may have multiple events on presentation, or develop them rapidly over days to weeks. Several disorders can present with this extreme clinical phenotype, including catastrophic antiphospholipid syndrome (APS), atypical presentations of thrombotic thrombocytopenic purpura (TTP) or heparin-induced thrombocytopenia (HIT), and Trousseau syndrome, but some patients present with multiple thrombotic events in the absence of associated prothrombotic disorders. Diagnostic workup must rapidly determine which, if any, of these syndromes are present because therapeutic management is driven by the underlying disorder. With the exception of atypical presentations of TTP, which are treated with plasma exchange, anticoagulation is the most important therapeutic intervention in these patients. Effective anticoagulation may require laboratory confirmation with anti–factor Xa levels in patients treated with heparin, especially if the baseline (pretreatment) activated partial thromboplastin time is prolonged. Patients with catastrophic APS also benefit from immunosuppressive therapy and/or plasma exchange, whereas patients with HIT need an alternative anticoagulant to replace heparin. Progressive thrombotic events despite therapeutic anticoagulation may necessitate an alternative therapeutic strategy. If the thrombotic process can be controlled, these patients can recover, but indefinite anticoagulant therapy may be appropriate to prevent recurrent events.

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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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Novel protein C gene mutation in a compound heterozygote resulting in catastrophic thrombosis in early adulthood: diagnosis and long‐term treatment with subcutaneous protein C concentrate

Cited by 16 publications

References 11 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

How I treat catastrophic thrombotic syndromes

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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