Severe congenital protein C deficiency: the use of protein C concentrates (human) as replacement therapy for life-threatening blood-clotting complications
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Abstract
The protein C pathway has an important function in regulating and modulating blood
coagulation and ensuring patency of the microcirculation. Protein C deficiency leads
to macro- and microvascular thrombosis. Congenital severe protein C deficiency is
a life-threatening state with neonatal purpura fulminans and pronounced coagulopathy.
Patients with heterozygous protein C deficiency have an increased risk for thromboembolic
events or experience coumarin-induced skin necrosis during initiation of coumarin
therapy. Replacement with protein C concentrates is an established therapy of congenital
protein C deficiency, resulting in rapid resolving of coagulopathy and thrombosis
without reasonable side effects. This article summarizes the current knowledge on
protein C replacement therapy in congenital protein C deficiency.
Protein C is best known for its mild deficiency associated with venous thrombosis risk and severe deficiency associated with neonatal purpura fulminans. Activated protein C (APC) anticoagulant activity involves proteolytic inactivation of factors Va and VIIIa, and APC resistance is often caused by factor V Leiden. Less known is the clinical success of APC in reducing mortality in severe sepsis patients (PROWESS trial) that gave impetus to new directions for basic and preclinical research on APC. This review summarizes insights gleaned from recent in vitro and in vivo studies of the direct cytoprotective effects of APC that include beneficial alterations in gene expression profiles, anti-inflammatory actions, antiapoptotic activities, and stabilization of endothelial barriers. APC's cytoprotection requires its receptor, endothelial cell protein C receptor, and protease-activated receptor-1. Because of its pleiotropic activities, APC has potential roles in the treatment of complex disorders, including sepsis, thrombosis, and ischemic stroke. Although much about molecular mechanisms for APC's effects on cells remains unclear, it is clear that APC's structural features mediating anticoagulant actions and related bleeding risks are distinct from those mediating cytoprotective actions, suggesting the possibility of developing APC variants with an improved profile for the ratio of cytoprotective to anticoagulant actions.
The coagulant and inflammatory exacerbation in sepsis is counterbalanced by the protective protein C (PC) pathway. Activated PC (APC) was shown to use the endothelial cell PC receptor (EPCR) as a coreceptor for cleavage of protease activated receptor 1 (PAR1) on endothelial cells. Gene profiling demonstrated that PAR1 signaling could account for all APC-induced protective genes, including the immunomodulatory monocyte chemoattractant protein-1 (MCP-1), which was selectively induced by activation of PAR1, but not PAR2. Thus, the prototypical thrombin receptor is the target for EPCR-dependent APC signaling, suggesting a role for this receptor cascade in protection from sepsis.
The protein C anticoagulant pathway serves as a major system for controlling thrombosis, limiting inflammatory responses, and potentially decreasing endothelial cell apoptosis in response to inflammatory cytokines and ischemia. The essential components of the pathway involve thrombin, thrombomodulin, the endothelial cell protein C receptor (EPCR), protein C, and protein S. Thrombomodulin binds thrombin, directly inhibiting its clotting and cell activation potential while at the same time augmenting protein C (and thrombin activatable fibrinolysis inhibitor [TAFI]) activation. Furthermore, thrombin bound to thrombomodulin is inactivated by plasma protease inhibitors > 20 times faster than free thrombin, resulting in increased clearance of thrombin from the circulation. The inhibited thrombin rapidly dissociates from thrombomodulin, regenerating the anticoagulant surface. Thrombomodulin also has direct anti-inflammatory activity, minimizing cytokine formation in the endothelium and decreasing leukocyte-endothelial cell adhesion. EPCR augments protein C activation approximately 20-fold in vivo by binding protein C and presenting it to the thrombin-thrombomodulin activation complex. Activated protein C (APC) retains its ability to bind EPCR, and this complex appears to be involved in some of the cellular signaling mechanisms that down-regulate inflammatory cytokine formation (tumor necrosis factor, interleukin-6). Once APC dissociates from EPCR, it binds to protein S on appropriate cell surfaces where it inactivates factors Va and VIIIa, thereby inhibiting further thrombin generation. Clinical studies reveal that deficiencies of protein C lead to microvascular thrombosis (purpura fulminans). During severe sepsis, a combination of protein C consumption, protein S inactivation, and reduction in activity of the activation complex by oxidation, cytokine-mediated down-regulation, and proteolytic release of the activation components sets in motion conditions that would favor an acquired defect in the protein C pathway, which in turn favors microvascular thrombosis, increased leukocyte adhesion, and increased cytokine formation. APC has been shown clinically to protect patients with severe sepsis. Protein C and thrombomodulin are in early stage clinical trials for this disease, and each has distinct potential advantages and disadvantages relative to APC.
Journal ID (publisher-id): Biologics: Targets & Therapy
Title:
Biologics : Targets & Therapy
Publisher:
Dove Medical Press
ISSN
(Print):
1177-5475
ISSN
(Electronic):
1177-5491
Publication date
(Print):
June
2008
Publication date
(Electronic):
June
2008
Volume: 2
Issue: 2
Pages: 285-296
Affiliations
Department of Medicine 1, Division Hematology and Hemostasis, Medical University of
Vienna, Vienna, Austria
Author notes
Correspondence: Paul N Knoebl, Medical University of Vienna, Department of Medicine
1, Division Hematology and Hemostasis, Waehringer Guertel 18-20, A-1090 Vienna, Austria,
Tel +43 1 40400 4410, Fax +43 1 40400 4030, Email
paul.knoebl@
123456meduniwien.ac.at
