Collagen‐mediated hemostasis

Manon‐Jensen, Tina; Kjeld, N.G.; Karsdal, Morten A.

doi:10.1111/jth.13249

Cited by 139 publications

(107 citation statements)

References 93 publications

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“…However, only three collagen variants were classified as probable pathogenic class 4 variants in patients fulfilling the clinical criteria of autosomal dominant inherited EDS. Collagen mediates platelet adhesion and activation following injury to the vascular wall and is essential for the maintenance of haemostasis (Manon‐Jensen et al , 2016). It is currently unclear whether collagen missense variants are causal of the bleeding tendency in patients not fulfilling the clinical EDS criteria.…”

Section: Discussionmentioning

confidence: 99%

Application of whole‐exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

et al. 2017

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SummaryRare inherited bleeding disorders (IBD) are a common cause of bleeding tendency. To ensure a correct diagnosis, specialized laboratory analyses are necessary. This study reports the results of an upfront diagnostic strategy using targeted whole exome sequencing. In total, 156 patients with a significant bleeding assessment tool score participated in the study, of which a third had thrombocytopenia. Eighty‐seven genes specifically associated with genetic predisposition to bleeding were analysed by whole exome sequencing. Variants were classified according to the five‐tier scheme. We identified 353 germline variants. Eight patients (5%) harboured a known pathogenic variant. Of the 345 previously unknown variants, computational analyses predicted 99 to be significant. Further filtration according to the Mendelian inheritance pattern, resulted in 59 variants being predicted to be clinically significant. Moreover, 34% (20/59) were assigned as novel class 4 or 5 variants upon targeted functional testing. A class 4 or 5 variant was identified in 30% of patients with thrombocytopenia (14/47) versus 11% of patients with a normal platelet count (12/109) (P < 0·01). An IBD diagnosis has a major clinical impact. The genetic investigations detailed here extricated our patients from a diagnostic conundrum, thus demonstrating that continuous optimization of the diagnostic work‐up of IBD is of great benefit.

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Section: Discussionmentioning

confidence: 99%

Application of whole‐exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

et al. 2017

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“…7,16,38,49 The most common substrate is type I collagen, which is found in the vascular wall and is a strong platelet agonist and initiator of the intrinsic pathway of coagulation via activation of factor XII. 22,46 Immobilized TF is used to introduce the extrinsic pathway, which tends to result in higher concentration of thrombin and more pronounced fibrin deposition. 28,31,32 These assays are typically performed at a constant flow rate to achieve a desired wall shear rate.…”

Section: Introductionmentioning

confidence: 99%

A Microfluidic Model of Hemostasis Sensitive to Platelet Function and Coagulation

et al. 2016

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Hemostasis is the process of sealing a vascular injury with a thrombus to arrest bleeding. The type of thrombus that forms depends on the nature of the injury and hemodynamics. There are many models of intravascular thrombus formation whereby blood is exposed to prothrombotic molecules on a solid substrate. However, there are few models of extravascular thrombus formation whereby blood escapes into the extravascular space through a hole in the vessel wall. Here, we describe a microfluidic model of hemostasis that includes vascular, vessel wall, and extravascular compartments. Type I collagen and tissue factor, which support platelet adhesion and initiate coagulation, respectively, were adsorbed to the wall of the injury channel and act synergistically to yield a stable thrombus that stops blood loss into the extravascular compartment in ~7.5 min. Inhibiting factor VIII to mimic hemophilia A results in an unstable thrombus that was unable to close the injury. Treatment with a P2Y12 antagonist to reduce platelet activation prolonged the closure time two-fold compared to controls. Taken together, these data demonstrate a hemostatic model that is sensitive to both coagulation and platelet function and can be used to study coagulopathies and platelet dysfunction that result in excessive blood loss.

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“…1). Regardless of the initial events, a common feature of all fibrotic diseases is the activation of ECM-producing cells, one of the key processes in the tissue remodeling seen in fibrosis (Kisseleva and Brenner 2008;Manon-Jensen et al 2016;Wynn 2008;Wynn and Ramalingam 2012). In this review, we will focus on fibroblasts as the archetypal ECM-producing cells, although a wide variety of other cell types in different tissues can also secrete collagens such as, for example, smooth muscle cells, pericytes and mesangial cells.…”

Section: Introductionmentioning

confidence: 98%

Contribution of collagen adhesion receptors to tissue fibrosis

Coelho

McCulloch

2016

Cell Tissue Res

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Fibrosis is the result of a wound-healing response that fails to restore normal tissue structure function. One of the critical hallmarks of fibrosis is disrupted collagen remodeling. In tissue homeostasis, the production, deposition and organization of collagen is balanced by the degradation and remodeling of collagen within the existing matrix. After injury or chronic infection, tissues initiate a wound-healing response that is intended to create a new ECM for restoring tissue structure and function. If the wound-healing response is dysregulated or if the tissue injury or infection is severe or long-lasting, collagen deposition exceeds collagen degradation and the tissue repair process leads to fibrosis. The fibrotic repair response is extraordinarily complex and involves a wide spectrum of cells, signaling pathways and regulatory systems, some of which can be readily disrupted and thereby contribute to fibrotic lesions. The dysregulated collagen remodeling is a common end-point of all fibrotic disorders, and one of the rate-limiting steps of collagen remodeling is the binding of cells to collagen fibrils by specific cell adhesion receptors. In this review, we describe how the expression and function of collagen adhesion receptors contribute to collagen processing events that contribute to tissue fibrosis. Graphical abstract Balance between collagen remodeling in health and disease.

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Collagen‐mediated hemostasis

Cited by 139 publications

References 93 publications

Application of whole‐exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

Application of whole‐exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

A Microfluidic Model of Hemostasis Sensitive to Platelet Function and Coagulation

Contribution of collagen adhesion receptors to tissue fibrosis

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