Treatment of Homozygous Protein C Deficiency and Neonatal Purpura Fulminans with a Purified Protein C Concentrate

Dreyfus, Marie; Jf, Magny; Bridey, Françoise; Schwarz, Hans; Planché, C; Dehan, M; Tchernia, G

doi:10.1056/nejm199111283252207

Cited by 268 publications

(137 citation statements)

References 15 publications

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“…In fact, APC infusions have been administered successfully in cases of PC deficiency (42) and in the treatment of meningococcemia (43), DIC (44), and severe sepsis (8). The use of a SERPIN-resistant APC therapy could enhance its utility further, especially in disease states characterized by elevated levels of the SERPINs.…”

Section: Discussionmentioning

confidence: 99%

Engineering the proteolytic specificity of activated protein C improves its pharmacological properties

Berg

Gerlitz²,

Shang³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Human activated protein C (APC) is an antithrombotic, antiinflammatory serine protease that plays a central role in vascular homeostasis, and activated recombinant protein C, drotrecogin alfa (activated), has been shown to reduce mortality in patients with severe sepsis. Similar to other serine proteases, functional APC levels are regulated by the serine protease inhibitor family of proteins including ␣1-antitrypsin and protein C inhibitor. Using APC-substrate modeling, we designed and produced a number of derivatives with the goal of altering the proteolytic specificity of APC such that the variants exhibited resistance to inactivation by protein C inhibitor and ␣1-antitrypsin yet maintained their primary anticoagulant activity. Substitutions at Leu-194 were of particular interest, because they exhibited 4-to 6-fold reductions in the rate of inactivation in human plasma and substantially increased pharmacokinetic profiles compared with wild-type APC. This was achieved with minimal impairment of the anticoagulant͞ antithrombotic activity of APC. These data demonstrate the ability to selectively modulate substrate specificity and subsequently affect in vivo performance and suggest therapeutic opportunities for the use of protein C derivatives in disease states with elevated serine protease inhibitor levels.

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Section: Discussionmentioning

confidence: 99%

Engineering the proteolytic specificity of activated protein C improves its pharmacological properties

Berg

Gerlitz²,

Shang³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…40,81,82 T h i s c o n d i t i o n i m p r o v e s w i t h t h e administration of protein C (60 IU/kg every 6-8 hours, with a subsequent customized dose adjustment) or, if this approach fails, fresh frozen plasma (10-20 mL/kg every 8-12 hours). For protein S deficiency, replacement therapy is done using fresh frozen plasma.…”

Section: Purpura Fulminansmentioning

confidence: 99%

Thrombosis in newborn infants

Bacciedoni

Attie

Donato³

et al. 2016

Arch Argent Pediat

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The incidence of thrombosis is higher among newborn infants than in any other stage of pediatric development. This fact is the consequence of labile characteristics of the neonatal hemostatic system, in addition to exposure to multiple risk factors and the wide use of vascular catheters. Venous thromboses, which mainly affect the limbs, the right atrium and renal veins, are more frequently seen than arterial thromboses. A stroke may be caused by the occlusion of the arterial flow entering the brain or by occlusion of its venous drainage system. Purpura fulminans is a very severe condition that should be treated as a medical emergency, and is secondary to severe protein C deficiency or, less frequently, protein S or antithrombin deficiency. Most thrombotic events should be managed with antithrombotic therapy, which is done with unfractionated and/or low molecular weight heparins. Purpura fulminans requires protein C replacement and/or fresh frozen plasma infusion. Thrombolytic therapy is done using tissue plasminogen activator and should only be used for life-, or limb-, or organthreatening thrombosis.

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“…68,69 As in adults, it has to be kept in mind that heparin administration as well as the use of thrombolytic agents can lead to major bleeding episodes or to acute thrombus rupture with subsequent pulmonary embolism or thromboembolic stroke in neonates (patent foramen ovale). In addition, heparin-induced thrombocytopenia type II has been reported not only in adults but also in paediatric patients, creating the potential need to substitute heparin with an alternative anticoagulant emergently.…”

Section: Acute Thrombotic Therapymentioning

confidence: 99%

Maternal thrombophilia and neonatal thrombosis

Heller

Nowak‐Göttl

2003

Best Practice & Research Clinical Haematology

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In neonates and infants, numerous clinical and environmental conditions lead to elevated thrombin generation and subsequent thrombus formation. Genetic prothrombotic defects (protein C, protein S and antithrombin deficiency, mutations of coagulation factor V and factor II, elevated lipoprotein (a)) have been established as risk factors of thromboembolic events in neonates and infants. The interpretation of the laboratory evaluation relies on age-dependent normal reference values. Because appropriate clinical trials are missing in these age groups, treatment recommendations are adapted from small-scale studies in neonates and infants and from guidelines relating to adult patient protocols. Secondary long-term anticoagulation should be administered on an individual basis.

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Treatment of Homozygous Protein C Deficiency and Neonatal Purpura Fulminans with a Purified Protein C Concentrate

Cited by 268 publications

References 15 publications

Engineering the proteolytic specificity of activated protein C improves its pharmacological properties

Engineering the proteolytic specificity of activated protein C improves its pharmacological properties

Thrombosis in newborn infants

Maternal thrombophilia and neonatal thrombosis

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