APC resistance: biological basis and acquired influences

Castoldi, Elisabetta; Rosing, Jan

doi:10.1111/j.1538-7836.2009.03711.x

Cited by 108 publications

(98 citation statements)

References 107 publications

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“…In an endogenous thrombin potential (ETP)-based assay, the vast majority of FVL-independent APC resistance was attributable to oral contraceptive use or pregnancy. 71 A similar mechanism is likely for obesity, which also posed a higher risk for DVT than PE. In the MEGA study, APC resistance increased linearly with increasing BMI in subjects without FVL.…”

Section: Discussionmentioning

confidence: 97%

Broadening the factor V Leiden paradox: pulmonary embolism and deep-vein thrombosis as 2 sides of the spectrum

Langevelde¹,

Flinterman²,

Vlieg³

et al. 2012

Blood

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AbstractRisk factors for deep-vein thrombosis have been shown not to be always the same as for pulmonary embolism. A well-known example is the factor V Leiden (FVL) paradox: the FVL mutation poses a clearly higher risk for deep-vein thrombosis (DVT) than for pulmonary embolism. We aimed to expand this paradox and therefore present risk estimates for several established risk factors for DVT and pulmonary embolism separately. When such separate risk estimates could not be retrieved from the literature, we calculated these risks in our own data, a large population-based case-control study on venous thrombosis (the MEGA study). Our results showed that the FVL paradox can be broadened (ie, the risk factors oral contraceptive use, pregnancy, puerperium, minor leg injuries, and obesity have an effect comparable with FVL). Furthermore, we found that pulmonary conditions, such as chronic obstructive pulmonary disease, pneumonia, and sickle cell disease, were risk factors with an opposite effect: a higher risk of pulmonary embolism, but little or no effect on DVT. These findings suggest that pulmonary embolism and DVT may not always have the same etiology, and encourage unraveling this phenomenon in further studies.

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Section: Discussionmentioning

confidence: 97%

Broadening the factor V Leiden paradox: pulmonary embolism and deep-vein thrombosis as 2 sides of the spectrum

Langevelde¹,

Flinterman²,

Vlieg³

et al. 2012

Blood

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“…95 Cosmetic disfigurement caused by scars often leads patients to suffer from psychosocial and social issues, which, in turn, results in a decreased quality of life. Scars are composed of the same ECM molecules as the tissue they replace, but the ratios in scar tissue are different to normal tissue.…”

Section: Abnormal Cutaneous Scar Typesmentioning

confidence: 99%

Extracellular Matrix Reorganization During Wound Healing and Its Impact on Abnormal Scarring

Xue

Jackson

2015

Advances in Wound Care

1,033

866

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Significance: When a cutaneous injury occurs, the wound heals via a dynamic series of physiological events, including coagulation, granulation tissue formation, re-epithelialization, and extracellular matrix (ECM) remodeling. The final stage can take many months, yet the new ECM forms a scar that never achieves the flexibility or strength of the original tissue. In certain circumstances, the normal scar is replaced by pathological fibrotic tissue, which results in hypertrophic or keloid scars. These scars cause significant morbidity through physical dysfunction and psychological stress. Recent Advances and Critical Issues: The cutaneous ECM comprises a complex assortment of proteins that was traditionally thought to simply provide structural integrity and scaffolding characteristics. However, recent findings show that the ECM has multiple functions, including, storage and delivery of growth factors and cytokines, tissue repair and various physiological functions. Abnormal ECM reconstruction during wound healing contributes to the formation of hypertrophic and keloid scars. Whereas adult wounds heal with scarring, the developing foetus has the ability to heal wounds in a scarless fashion by regenerating skin and restoring the normal ECM architecture, strength, and function. Recent studies show that the lack of inflammation in fetal wounds contributes to this perfect healing. Future Directions: Better understanding of the exact roles of ECM components in scarring will allow us to produce therapeutic agents to prevent hypertrophic and keloid scars. This review will focus on the components of the ECM and their role in both physiological and pathological (hypertrophic and keloid) cutaneous scar formation. SCOPE AND SIGNIFICANCEThis article reviews the extracellular matrix (ECM) and its remodeling during normal cutaneous wound healing and scar formation, and the differential response of the components of the ECM and their role in pathological (hypertrophic and keloid) cutaneous scar formation. This review focuses on the major players involved in the irregular ECM production as being; fibroblasts and their immature counterparts, myofibroblasts; collagens; transforming growth factor (TGF)-b, which controls the production of collagens; proteoglycans and matrix metalloproteinases (MMPs). We also highlight the complexity of interactions occurring in the ECM of skin during (ab) normal scar formation. TRANSLATIONAL RELEVANCEAbnormal ECM, particularly abnormal collagen remodeling and reorganization, accounts for one of the most important contributing factors to abnormal scarring. Identification of the exact ECM molecules involved in causing abnormal scarring is likely to provide a future treatment target. This may be achieved by promoting the correct balance in collagen ratios or by directly targeting the production of collagen. Overall, a better understanding of the exact roles of ECM components in scarring will help us to produce therapeutic agents to prevent and treat hypertrophic and keloid scars. CLINICAL RELEVANCEThere ...

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“…Potential candidate mechanisms that do not involve the degradation of fVa or fVIIIa but are consistent with known functions of pS and fV include (1) the destabilization of the signaling-competent conformation of the TF complex secondary to physical interactions of B domain-containing fVa with fXa 49 and of pS with TF and fXa 50 , and/or (2) the recruitment of TF pathway inhibitor a (TFPIa) to the TF-fVIIa-fXa complex via interaction of pS with the TFPIa K3 domain or of the fV B domain with the carboxyterminal fragment of TFPIa (reviewed in Wood et al 51 ). It also remains to be clarified whether other naturally occurring fV variants such as fV Liverpool (I359T), 52 fV Nara (W1920R), 53 fV released from platelets, 54 or fV present in homozygous carriers of the fV R2 haplotype 11,[55][56][57] would exhibit similarly defective cofactor function for the inhibition of TF signaling by aPC as does fV Leiden.…”

Section: Discussionmentioning

confidence: 99%

“…The fV cofactor form is generated by cleavage of intact procofactor V by aPC at R506 and facilitates (in cooperation with pS) the proteolytic degradation of fVa and fVIIIa. The mechanistic and structural details of these interactions are only partially characterized, and may involve an as-yet-hypothetical trimolecular complex of aPC-cleaved fV, pS, and aPC (reviewed in Dahlbäck and Villoutreix, 3 Castoldi and Rosing, 11 and Cramer and Gale 12 ). The naturally occurring R506Q Leiden mutation in fV (fV Leiden) largely abrogates the anticoagulant functions of aPC not only by rendering fVa partially refractory to aPC proteolysis but also by preventing the formation of the anticoagulant cofactor form of fV.…”

Section: Introductionmentioning

confidence: 99%

Coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice

Liang

Kerschen

Basu

et al. 2015

Blood

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Key Points• Factor V and protein S are required for sepsis mortality reduction and suppression of inflammatory gene expression by activated protein C.• The R506Q mutation (Leiden mutation) abrogates the antiinflammatory cofactor function of factor V for activated protein C.The key effector molecule of the natural protein C pathway, activated protein C (aPC), exerts pleiotropic effects on coagulation, fibrinolysis, and inflammation. Coagulation-independent cell signaling by aPC appears to be the predominant mechanism underlying its highly reproducible therapeutic efficacy in most animal models of injury and infection. In this study, using a mouse model of Staphylococcus aureus sepsis, we demonstrate marked disease stage-specific effects of the anticoagulant and cell signaling functions of aPC. aPC resistance of factor (f)V due to the R506Q Leiden mutation protected against detrimental anticoagulant effects of aPC therapy but also abrogated the anti-inflammatory and mortalityreducing effects of the signaling-selective 5A-aPC variant that has minimal anticoagulant function. We found that procofactor V (cleaved by aPC at R506) and protein S were necessary cofactors for the aPC-mediated inhibition of inflammatory tissue-factor signaling. The antiinflammatory cofactor function of fV involved the same structural features that govern its cofactor function for the anticoagulant effects of aPC, yet its anti-inflammatory activities did not involve proteolysis of activated coagulation factors Va and VIIIa. These findings reveal a novel biological function and mechanism of the protein C pathway in which protein S and the aPC-cleaved form of fV are cofactors for anti-inflammatory cell signaling by aPC in the context of endotoxemia and infection. (Blood. 2015;126(21):2415-2423 Introduction Natural aPC exerts pleiotropic effects on coagulation, fibrinolysis, and inflammation (for review, see Esmon, 1 Mosnier and Griffin,2 and Dahlbäck and Villoutreix 3 ) that are predominantly mediated by 2 mechanistically discernable pathways: (1) aPC degrades activated coagulation factor (f)Va and fVIIIa to curtail the formation of thrombin by the plasma coagulation system and (2) when bound to the endothelial protein C receptor (EPCR, ProcR) or the integrin aMb2 (Mac1)(CD11b/CD18), aPC becomes competent for activating the G protein-coupled protease activated receptor (PAR) 1, 2, or 3. PAR activation and crosstalk with other receptors mediate anti-inflammatory and cytoprotective effects of aPC in innate immune cells, vascular endothelium, and other cells (for review, see Weiler,4 Mosnier et al, 5 and Dahlbäck and Villoutreix 6). In animal models of endotoxemia and sepsis, the cell signaling activity of aPC on vascular endothelium and innate immune cells is the predominant therapeutic mechanism of action, and recombinant variants of aPC that are largely devoid of anticoagulant activity but retain signaling function confer vasoprotection, inhibit inflammation, and reduce mortality. 7-9 Although the incidence of microvascular coagulopathies in p...

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APC resistance: biological basis and acquired influences

Cited by 108 publications

References 107 publications

Broadening the factor V Leiden paradox: pulmonary embolism and deep-vein thrombosis as 2 sides of the spectrum

Broadening the factor V Leiden paradox: pulmonary embolism and deep-vein thrombosis as 2 sides of the spectrum

Extracellular Matrix Reorganization During Wound Healing and Its Impact on Abnormal Scarring

Coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice

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