Non-activated plasma-derived PC improves amputation rate of children undergoing sepsis

Piccin, Andrea; Marcaigh, Aengus Oʼ; Mahon, Corrina Mc; Murphy, Ciaran; Okafor, Ikechukwu; Marcheselli, Luigi; Casey, William; Claffey, L. P.; Smith, Owen

doi:10.1016/j.thromres.2014.04.019

Cited by 9 publications

(7 citation statements)

References 16 publications

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“…Our group already showed reduced PC and free-PS levels in children in steady state with further reduction in crisis ( 18 ). Although reduced PC levels are not as dramatic as those reported in sepsis ( 44 ), nevertheless this warrants further investigations. Early reports of a benefit of tinzaparin in SCA patients also support these findings ( 45 ).…”

Section: Discussionmentioning

confidence: 60%

Circulating microparticles, protein C, free protein S and endothelial vascular markers in children with sickle cell anaemia

Piccin

Murphy

Eakins

et al. 2015

J of Extracellular Vesicle

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IntroductionCirculating microparticles (MP) have been described in sickle cell anaemia (SCA); however, their interaction with endothelial markers remains unclear. We investigated the relationship between MP, protein C (PC), free protein S (PS), nitric oxide (NO), endothelin-1 (ET-1) and adrenomedullin (ADM) in a large cohort of paediatric patients.MethodA total of 111 children of African ethnicity with SCA: 51 in steady state; 15 in crises; 30 on hydroxyurea (HU) therapy; 15 on transfusion; 17 controls (HbAA) of similar age/ethnicity. MP were analysed by flow cytometry using: Annexin V (AV), CD61, CD42a, CD62P, CD235a, CD14, CD142 (tissue factor), CD201 (endothelial PC receptor), CD62E, CD36 (TSP-1), CD47 (TSP-1 receptor), CD31 (PECAM), CD144 (VE-cadherin). Protein C, free PS, NO, pro-ADM and C-terminal ET-1 were also measured.ResultsTotal MP AV was lower in crisis (1.26×106 ml−1; 0.56–2.44×106) and steady state (1.35×106 ml−1; 0.71–3.0×106) compared to transfusion (4.33×106 ml−1; 1.6–9.2×106, p<0.01). Protein C levels were significantly lower in crisis (median 0.52 IU ml−1; interquartile range 0.43–0.62) compared with all other groups: HbAA (0.72 IU ml−1; 0.66–0.82, p<0.001); HU (0.67 IU ml−1; 0.58–0.77, p<0.001); steady state (0.63 IU ml−1; 0.54–0.70, p<0.05) and transfusion (0.60 IU ml−1; 0.54–0.70, p<0.05). In addition, levels were significantly reduced in steady state (0.63 IU ml−1; 0.54–0.70) compared with HbAA (0.72 IU ml−1; 0.66–0.80, p<0.01). PS levels were significantly higher in HbAA (0.85 IU ml−1; 0.72–0.97) compared with crisis (0.49 IU ml−1; 0.42–0.64, p<0.001), HU (0.65 IU ml−1; 0.56–0.74, p<0.01) and transfusion (0.59 IU ml−1; 0.47–0.71, p<0.01). There was also a significant difference in crisis patients compared with steady state (0.49 IU ml−1; 0.42–0.64 vs. 0.68 IU ml−1; 0.58–0.79, p<0.05). There was high correlation (R>0.9, p<0.05) between total numbers of AV-positive MP (MP AV) and platelet MP expressing non-activation platelet markers. There was a lower correlation between MP AV and MP CD62P (R=0.73, p<0.05) (platelet activation marker), and also a lower correlation between percentage of MP expressing CD201 (%MP CD201) and %MP CD14 (R=0.627, p<0.001). %MP CD201 was higher in crisis (11.6%) compared with HbAA (3.2%, p<0.05); %MP CD144 was higher in crisis (7.6%) compared with transfusion (2.1%, p<0.05); %CD14 (0.77%) was higher in crisis compared with transfusion (0.0%, p<0.05) and steady state (0.0%, p<0.01); MP CD14 was detectable in a higher number of samples (92%) in crisis compared with the rest (40%); %MP CD235a was higher in crisis (17.9%) compared with transfusion (8.9%), HU (8.7%) and steady state (9.9%, p<0.05); %CD62E did not differ significantly across the groups and CD142 was undetectable. Pro-ADM levels were raised in chest crisis: 0.38 nmol L−1 (0.31–0.49) versus steady state: 0.27 nmol L−1 (0.25–0.32; p<0.01) and control: 0.28 nmol L−1 (0.27–0.31; p<0.01). CT-proET-1 levels were reduced in patients on HU therapy: 43.6 pmol L−1 (12.6–49.6) versus control: 55.1 pmol L−1 (45.2–63....

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Section: Discussionmentioning

confidence: 60%

Circulating microparticles, protein C, free protein S and endothelial vascular markers in children with sickle cell anaemia

Piccin

Murphy

Eakins

et al. 2015

J of Extracellular Vesicle

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“…Some experts advise early protein C replacement therapy in patients with severe meningococcemia. 68,69 However, in order to become activated, protein C requires the presence of thrombomodulin on the surface of endothelial cells (Fig. 1C).…”

Section: Treatmentmentioning

confidence: 99%

Ischemic Limb Gangrene with Pulses

2015

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“…This study was extremely original and innovative since, in spite of the recent widening of the off-label indications in pediatric [20,21,27,28] and adult [19] patients, no randomized, placebo-controlled trial in critically ill pediatric or adult patients has ever investigated clinically relevant endpoints. Another unique feature of our trial is that it enrolled patients admitted to the ICU for a primary disorder other than sepsis (mostly cardiac pathology or acute lung failure).…”

Section: Key Findingsmentioning

confidence: 99%

“…No bleeding complications related to the study drug were reported, and most studies underlined normalization of inflammatory markers and of coagulation abnormalities. Notably, recent case reports suggest that the use of protein C zymogen is widespread in in other clinical settings such as adult solid tumors, oncohematology, and pediatric amputations [19,20,27].…”

Section: Previous Relevant Studiesmentioning

confidence: 99%

“…At the clinical level, protein C zymogen has been administered to more than 340 patients with congenital protein C deficits without any bleeding or allergic complications, and with improvements in coagulation abnormalities [16]. Recent reports suggest that its use is expanding in other settings [19][20][21]. However, the absence of a randomized clinical trial (RCT) leaves clinicians uncertain as to whether protein C zymogen, an expensive drug, should be prescribed in adult patients with severe sepsis and septic shock to improve clinically relevant outcomes.…”

Section: Introductionmentioning

confidence: 99%

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Protein C zymogen in severe sepsis: a double-blinded, placebo-controlled, randomized study

et al. 2016

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Non-activated plasma-derived PC improves amputation rate of children undergoing sepsis

Cited by 9 publications

References 16 publications

Circulating microparticles, protein C, free protein S and endothelial vascular markers in children with sickle cell anaemia

Circulating microparticles, protein C, free protein S and endothelial vascular markers in children with sickle cell anaemia

Ischemic Limb Gangrene with Pulses

Protein C zymogen in severe sepsis: a double-blinded, placebo-controlled, randomized study

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