The factor V light chain mediates the binding and endocytosis of plasma‐derived factor V by megakaryocytes

Bouchard, Beth A.; Abdalla, Sarah; Tracy, Paula B.

doi:10.1111/jth.12417

Cited by 7 publications

(3 citation statements)

References 16 publications

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“…The ability of ex-vivo differentiated megakaryocytes to endocytose exogenous FV 43 allowed us to verify that mutant FV rescued with G418 and 2,6-DAP can be efficiently internalised, even at the very low concentration of 0.33 nM, corresponding to a plasma FV level of ~1.5%. This is consistent with FV uptake by megakaryocytes being mediated by the light chain, without involvement of the B-domain 64 .…”

Section: In Vitro and Ex Vivo Rescue Of A Nonsense Mutation Responsib...supporting

confidence: 87%

Genetic mechanisms of inherited bleeding disorders as a basis for personalised medicine approaches

Todaro

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Section: In Vitro and Ex Vivo Rescue Of A Nonsense Mutation Responsib...supporting

confidence: 87%

Genetic mechanisms of inherited bleeding disorders as a basis for personalised medicine approaches

Todaro

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“…Further investigations would be required, using platelet‐rich plasma, to identify the potential importance of platelets in the phenotypic differences observed. A report has recently demonstrated that the FV LCh mediates FV uptake by megakaryocytes , and this may offer an alternative/additional explanation for the fact that hemorrhagic patients have anti‐LCh antibodies.…”

Section: Discussionmentioning

confidence: 99%

Coagulation function and mechanisms in various clinical phenotypes of patients with acquired factor V inhibitors

Matsumoto

Nogami

Shima

2014

Journal of Thrombosis and Haemostasis

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Summary. Background: The clinical phenotype of individuals with acquired factor V (A-FV) inhibitors varies from asymptomatic (non-B group) to life-threatening bleeding (B group), but the mechanism(s) underlying this variation in hemorrhagic phenotype are poorly understood. Objective: To investigate coagulation mechanistically in a range of patients with A-FV antibodies. Methods and Results: Ten cases of A-FV inhibitors in the non-B (n = 5) and B groups (n = 5) were studied. Thrombin generation assays in these plasmas revealed little thrombin generation, despite similar FV activity levels in both groups. However, prothrombin time-based clot waveform analysis revealed that the clot times were significantly prolonged and the maximum velocity and acceleration of coagulation were lower in the B group than in the non-B group, suggesting that this technique might be useful for predicting and monitoring hemorrhagic symptoms. A-FV inhibitors from the non-B group recognized predominantly the FV heavy chain, whereas those from the B group recognized the light chain. Purified anti-FV autoantibodies (autoAbs) from the B group inhibited FV binding to phospholipid by 60-90%, whereas there was little effect on this reaction in the non-B group. In addition, anti-FV autoAbs from the non-B group impaired the activated protein C (APC) cofactor activity of FV in FVIIIa inactivation mechanisms, and delayed APC-catalyzed cleavage of FVa at Arg306, but not at Arg506, indicating the presence of APC resistance in the non-B group. Conclusions: The results suggest that the different hemorrhagic phenotypes in A-FV inhibitors depend on the specific epitope of anti-FV autoAbs, and appear to be associated with an imbalance of procoagulant and anticoagulant function.

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“…This facilitates binding of another factor V molecule to LRP‐1. In studies using various factor V molecules and monoclonal antibodies, it was demonstrated that factor V binding to and endocytosis by megakaryocytes are mediated by the factor V light chain (Bouchard et al, ) although the specific factor V regions and amino acid residues involved are unknown. Following its binding to LRP‐1, factor V is endocytosed in Ca 2+ ‐ and clathrin‐dependent manners.…”

Section: Platelet‐derived Factor V/va Forms the More Hemostatically Rmentioning

confidence: 99%

Mechanisms Regulating Acquisition of Platelet‐Derived Factor V/Va by Megakaryocytes

Gertz

Bouchard

2015

J of Cellular Biochemistry

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Factor Va serves as the nonenzymatic protein cofactor for the prothrombinase complex, which converts prothrombin to thrombin in the events leading to formation of a hemostatic plug. Several observations support the concept that platelet-derived factor V/Va is physically and functionally distinct and plays a more important role in thrombin generation at sites of vascular injury as compared to its plasma counterpart. Platelet-derived factor V/Va is generated following endocytosis of the plasma-derived molecule by the platelet precursor cells, megakaryocytes, via a two receptor system consisting of low density lipoprotein (LDL) receptor-related protein-1 (LRP-1) and an unidentified specific "binding site". More recently, it was suggested that a cell surface-expressed β-galactoside binding protein, galectin-8, was involved in factor V endocytosis. Endocytosed factor V is trafficked through the cell and retailored prior to its storage in α-granules. Given the essential role of platelet-derived factor Va in clot formation, understanding the cellular and molecular mechanisms that regulate how platelets acquire this molecule will be important for the treatment of excessive bleeding or clotting.

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The factor V light chain mediates the binding and endocytosis of plasma‐derived factor V by megakaryocytes

Cited by 7 publications

References 16 publications

Genetic mechanisms of inherited bleeding disorders as a basis for personalised medicine approaches

Genetic mechanisms of inherited bleeding disorders as a basis for personalised medicine approaches

Coagulation function and mechanisms in various clinical phenotypes of patients with acquired factor V inhibitors

Mechanisms Regulating Acquisition of Platelet‐Derived Factor V/Va by Megakaryocytes

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