Insights into platelet-based control of coagulation

Witt, Susanne; Verdoold, Remco; Cosemans, Judith M.E.M.; Heemskerk, Johan W. M.

doi:10.1016/s0049-3848(14)50024-2

Cited by 74 publications

(62 citation statements)

References 118 publications

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“…Our in vitro and in vivo analyses of thrombus formation induced by TMEM16F-null platelets suggested a role for TMEM16F in activation-induced PtdSer exposure, and supported the model in which Ca 2+ -induced PtdSer exposure is involved in the generation of thrombin and fibrin, but not clot retraction (16,17). Mice with the platelet-specific deletion of TMEM16F exhibited a phenotype similar to that of human patients with Scott syndrome, and may provide a useful model for this human disease.…”

supporting

confidence: 74%

“…Notably, Yang et al (13) activated mouse platelet at 37°C for 30 min and did not see clear TMEM16F dependency on PtdSer exposure. PtdSer exposure in activated mouse platelets is also mediated by cyclophilin D-dependent Ca 2+ -induced openings of the mitochondrial permeability transition pore (MPTP) (17,32). These changes in MPTP lead to cell death, and mouse platelets may undergo MPTP more easily than human platelets.…”

Section: Discussionmentioning

confidence: 99%

“…PtdSer exposed on the platelets serves as the membrane scaffold for tenase (Factors VIII and IX) and prothrombinase (Factors V and X), resulting in the generation of thrombin for blood clotting (17). To investigate the possible involvement of TMEM16F in thrombin generation, the tissue factor-induced thrombin generation was assayed at 20°C with platelet-free plasma (PFP) and washed TMEM16F-expressing or -deficient platelets.…”

Section: Significancementioning

confidence: 99%

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TMEM16F is required for phosphatidylserine exposure and microparticle release in activated mouse platelets

Fujii

Sakata

Nishimura

et al. 2015

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

196

171

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Phosphatidylserine (PtdSer) exposure on the surface of activated platelets requires the action of a phospholipid scramblase(s), and serves as a scaffold for the assembly of the tenase and prothrombinase complexes involved in blood coagulation. Here, we found that the activation of mouse platelets with thrombin/collagen or Ca2+ ionophore at 20 °C induces PtdSer exposure without compromising plasma membrane integrity. Among five transmembrane protein 16 (TMEM16) members that support Ca2+-dependent phospholipid scrambling, TMEM16F was the only one that showed high expression in mouse platelets. Platelets from platelet-specific TMEM16F-deficient mice exhibited defects in activation-induced PtdSer exposure and microparticle shedding, although α-granule and dense granule release remained intact. The rate of tissue factor-induced thrombin generation by TMEM16F-deficient platelets was severely reduced, whereas thrombin-induced clot retraction was unaffected. The imaging of laser-induced thrombus formation in whole animals showed that PtdSer exposure on aggregated platelets was TMEM16F-dependent in vivo. The phenotypes of the platelet-specific TMEM16F-null mice resemble those of patients with Scott syndrome, a mild bleeding disorder, indicating that these mice may provide a useful model for human Scott syndrome.

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supporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

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TMEM16F is required for phosphatidylserine exposure and microparticle release in activated mouse platelets

Fujii

Sakata

Nishimura

et al. 2015

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

196

171

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“…Both Atg5 and Beclin 1 are essential for apoptotic cell clearance during development by mediating expression of extracellular PS. 73 As PS exposure is also important for hemostasis, 74,75 we thought that autophagy-mediated PS exposure in platelets might be required for hemostasis. Unfortunately, this hypothesis is unlikely, as our studies with annexin V (data not shown) and lactadherin (supplemental Figure 5E) binding showed no impairment in activation-dependent PS exposure on Atg7 f/f ;PF4-Cre/1 platelets.…”

Section: Autophagy In Hemostasis and Thrombosis 1229mentioning

confidence: 99%

Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis

Ouseph

Huang

Banerjee

et al. 2015

Blood

120

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Key Points• Autophagy, an essential degradation pathway, is constitutively active in resting platelets and is induced upon platelet activation.• Platelet autophagy is indispensable for hemostasis and thrombus formation.Autophagy is important for maintaining cellular homeostasis, and thus its deficiency is implicated in a broad spectrum of human diseases. Its role in platelet function has only recently been examined. Our biochemical and imaging studies demonstrate that the core autophagy machinery exists in platelets, and that autophagy is constitutively active in resting platelets. Moreover, autophagy is induced upon platelet activation, as indicated by agonist-induced loss of the autophagy marker LC3II. Additional experiments, using inhibitors of platelet activation, proteases, and lysosomal acidification, as well as platelets from knockout mouse strains, show that agonist-induced LC3II loss is a consequence of platelet signaling cascades and requires proteases, acidic compartments, and membrane fusion. To assess the physiological role of platelet autophagy, we generated a mouse strain with a megakaryocyte-and platelet-specific deletion of Atg7, an enzyme required for LC3II production. Ex vivo analysis of platelets from these mice shows modest defects in aggregation and granule cargo packaging. Although these mice have normal platelet numbers and size distributions, they exhibit a robust bleeding diathesis in the tail-bleeding assay and a prolonged occlusion time in the FeCl 3 -induced carotid injury model. Our results demonstrate that autophagy occurs in platelets and is important for hemostasis and thrombosis. (Blood. 2015;126(10):1224-1233 Introduction Autophagy, one of the major degradation pathways in eukaryotes, is important for cellular homeostasis and is implicated in a broad spectrum of human diseases including cancer, neurodegeneration, and cardiovascular diseases.1 There are 3 main types: chaperone-mediated autophagy, 2 microautophagy, 3,4 and the primary form, macroautophagy (referred to hereafter as autophagy).5 Autophagy involves de novo synthesis of double-membraned organelles called autophagosomes that contain cytosolic constituents including damaged organelles (eg, mitochondria) and protein aggregates. Autophagosomes fuse with multivesicular bodies, late endosomes, and lysosomes to form autolysosomes, 6 in which waste elimination, energy production, and recycling of cellular components take place.Autophagosome biogenesis and maturation use several protein complexes. [7][8][9][10] In mammals, cellular signals (eg, starvation) activate the Ulk1 complex (Ulk1, FIP200, Atg13, and Atg101), 11-14 which together with syntaxin 17, 15 localizes Atg14/Atg14L [16][17][18][19] to the endoplasmic reticulum. 15,20 This recruits the Beclin 1-Vps34 core complex (Beclin 1, Vps34, and Vps15) to autophagosome initiation sites and promotes phosphatidylinositol 3-phosphate production for recruitment of additional autophagy pathway components.20,21 Two ubiquitin-like conjugation systems are also important for autoph...

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“…In thrombolysis, Fibrinogen, a prime protein causes fibrinolysis. It is soluble, complex multifunctional 340 kDa of 45 nm in length [2].…”

Section: Introductionmentioning

confidence: 99%

Fibrinolytic Enzyme: Restoration Tool for Obliteration of Blood Clots

Ashraf¹,

Meer²,

Naz³

et al. 2017

J Mol Imaging Dynam

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Body interrelated complex system maintain body hemostasis but severe vascular injury reprehensible for thrombus formation. Fibrinogen is a prime protein in fibrinolysis. Complex cascade pathway involves in conversion of plasminogen to plasmin to perform fibrinolysis and plasminogen activating inhibitor (PAI) cease this pathway. The genetic and acquired factors influence clot formation while it curbs by factor VIII. This review aims to illustrate significance of fibrinolytic enzymes, Nattokinase, Urokinase, Staphylokinase and streptokinase as therapeutic agent to control myocardial infraction, venous stroke and pulmonary clotting.

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Insights into platelet-based control of coagulation

Cited by 74 publications

References 118 publications

TMEM16F is required for phosphatidylserine exposure and microparticle release in activated mouse platelets

TMEM16F is required for phosphatidylserine exposure and microparticle release in activated mouse platelets

Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis

Fibrinolytic Enzyme: Restoration Tool for Obliteration of Blood Clots

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