Defective PDI release from platelets and endothelial cells impairs thrombus formation in Hermansky-Pudlak syndrome

Sharda, Anish V.; Kim, Sarah H.; Jasuja, Reema; Gopal, Srila; Flaumenhaft, Robert; Furie, Barbara C.; Furie, Bruce

doi:10.1182/blood-2014-08-597419

Cited by 58 publications

(55 citation statements)

References 31 publications

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“…Poole and colleagues showed that ADP addition overrides much of the α-granule secretion defect [72]. These data underline the fact that dense granule secretion deficiency precipitates defects in α-granule and lysosome release; a point that has been noted by others [73, 74]. Thus, the autocrine signaling from released ADP plays a critical role in modulating α-granule and lysosome release.…”

Section: Snare Regulatory Proteinsmentioning

confidence: 78%

The nuts and bolts of the platelet release reaction

Joshi

Whiteheart

2016

Platelets

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Secretion is essential to many of the roles that platelets play in the vasculature, e.g., thrombosis, angiogenesis, and inflammation, enabling platelets to modulate the microenvironment at sites of vascular lesions with a myriad of bioactive molecules stored in their granules. Past studies demonstrate that granule cargo release is mediated by Soluble NSF Attachment Protein Receptor (SNARE) proteins, which are required for granule-plasma membrane fusion. Several SNARE regulators, which control when, where, and how the SNAREs interact, have been identified in platelets. Additionally, platelet SNAREs are controlled by post-translational modifications, e.g., phosphorylation and acylation. Although there have been many recent insights into the mechanisms of platelet secretion, much still remains undefined. In this review, we focus on the mechanics of platelet secretion and discuss how the secretory machinery functions in the pathway leading to membrane fusion and cargo release.

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Section: Snare Regulatory Proteinsmentioning

confidence: 78%

The nuts and bolts of the platelet release reaction

Joshi

Whiteheart

2016

Platelets

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“…59 The core comprises tightly packed, degranulated platelets encased in fibrin. 59 ADP released from dense granules regulates a-granule secretion, [60][61][62] forming dense regions that stabilize the platelet aggregate. 63 Concomitant release of polyP with ADP from dense granules suggests that it may be retained in these low-solute transport areas.…”

Section: Discussionmentioning

confidence: 99%

Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity

Mitchell

Lionikiene

Georgiev

et al. 2016

Blood

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Key Points• PolyP significantly augments the plasminogen activator capacity of FXIIa.• Platelet-bound fibrin acts as a reservoir for plasminogen, FXII(a), and polyP.Activated factor XII (FXIIa) has plasminogen activator capacity but its relative contribution to fibrinolysis is considered marginal compared with urokinase and tissue plasminogen activator. Polyphosphate (polyP) is released from activated platelets and mediates FXII activation. Here, we investigate the contribution of polyP to the plasminogen activator function of aFXIIa. We show that both polyP 70 , of the chain length found in platelets (60-100 mer), and platelet-derived polyP significantly augment the plasminogen activation capacity of aFXIIa. PolyP 70 stimulated the autoactivation of FXII and subsequent plasminogen activation, indicating that once activated, aFXIIa remains bound to polyP 70 . Indeed, complex formation between polyP 70 and aFXIIa provides protection against autodegradation. Plasminogen activation by bFXIIa was minimal and not enhanced by polyP 70 , highlighting the importance of the anion binding site. PolyP 70 did not modulate plasmin activity but stimulated activation of Glu and Lys forms of plasminogen by aFXIIa. Accordingly, polyP 70 was found to bind to FXII, aFXIIa, and plasminogen, but not bFXIIa. Fibrin and polyP 70 acted synergistically to enhance aFXIIa-mediated plasminogen activation. The plasminogen activator activity of the aFXIIa-polyP 70 complex was modulated by C1 inhibitor and histidine-rich glycoprotein, but not plasminogen activator inhibitors 1 and 2. Platelet polyP and FXII were found to colocalize on the activated platelet membrane in a fibrin-dependent manner and decorated fibrin strands extending from platelet aggregates. We show that in the presence of platelet polyP and the downstream substrate fibrin, aFXIIa is a highly efficient and favorable plasminogen activator. Our data are the first to document a profibrinolytic function of platelet polyP. (Blood. 2016;128(24):2834-2845

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“…Platelets and endothelial cells from HPS mice are deficient in the secretion of PDI. 44 Furthermore, infusion of recombinant PDI reverses the thrombus formation defect in HPS mice (S. H. Kim and B. Furie, unpublished observations, 2013). Whether recombinant PDI shortens bleeding times in mice has not yet been determined.…”

Section: Thiol Isomerases In Coagulopathymentioning

confidence: 99%

“…41 Several other groups subsequently demonstrated that thiol isomerases traffic to secretory granules/membrane systems and are released from platelets in an activation-dependent manner. 36,[42][43][44][45] Kim et al showed that platelets lacking PDI have reduced activation-dependent aggregation. 46 Platelet surface PDI has been postulated to modulate a IIb b 3 function, 47 Thiol isomerases have also been found on the surface of the endothelium.…”

Section: Vascular Thiol Isomerasesmentioning

confidence: 99%

Vascular thiol isomerases

Flaumenhaft

Furie

2016

Blood

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Thiol isomerases are multifunctional enzymes that influence protein structure via their oxidoreductase, isomerase, and chaperone activities. These enzymes localize at high concentrations in the endoplasmic reticulum of all eukaryotic cells where they serve an essential function in folding nascent proteins. However, thiol isomerases can escape endoplasmic retention and be secreted and localized on plasma membranes. Several thiol isomerases including protein disulfide isomerase, ERp57, and ERp5 are secreted by and localize to the membranes of platelets and endothelial cells. These vascular thiol isomerases are released following vessel injury and participate in thrombus formation. Although most of the activities of vascular thiol isomerases that contribute to thrombus formation are yet to be defined at the molecular level, allosteric disulfide bonds that are modified by thiol isomerases have been described in substrates such as αIIbβ3, αvβ3, GPIbα, tissue factor, and thrombospondin. Vascular thiol isomerases also act as redox sensors. They respond to the local redox environment and influence S-nitrosylation of surface proteins on platelets and endothelial cells. Despite our rudimentary understanding of the mechanisms by which thiol isomerases control vascular function, the clinical utility of targeting them in thrombotic disorders is already being explored in clinical trials.

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Defective PDI release from platelets and endothelial cells impairs thrombus formation in Hermansky-Pudlak syndrome

Abstract: Key Points Hermansky-Pudlak syndrome exhibits impaired granule exocytosis and PDI secretion that contribute to its associated bleeding disorder. Endothelial cells deficient in HPS6 show defective secretion of granules, including Weibel-Palade bodies.

Cited by 58 publications

References 31 publications

The nuts and bolts of the platelet release reaction

The nuts and bolts of the platelet release reaction

Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity

Vascular thiol isomerases

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