Only severe thrombocytopenia results in bleeding and defective thrombus formation in mice

Morowski, Martina; Vögtle, Timo; Kraft, Peter; Kleinschnitz, Christoph; Stoll, Guido; Nieswandt, Bernhard

doi:10.1182/blood-2012-10-461459

Cited by 115 publications

(98 citation statements)

References 51 publications

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“…These findings were consistent across different genetic backgrounds of mice (N. Urtz, unpublished data, 2011). Consistent with previous reports, 30 dilution of blood from WT mice with platelet poor plasma was not sufficient to phenocopy the defect in platelet aggregation observed in Sphk2-deficient mice (N. Urtz, unpublished data, 2011), indicating that the reduced platelet numbers in these mutants are unlikely to be responsible for their defect in PAR4-P and ADPinduced aggregation. .…”

Section: Sphk2-deficient Platelets Reveal Impaired Aggregationsupporting

confidence: 90%

Sphingosine 1-Phosphate Produced by Sphingosine Kinase 2 Intrinsically Controls Platelet Aggregation In Vitro and In Vivo

Urtz

Gaertner

Bruehl

et al. 2015

Circulation Research

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Rationale: Platelets are known to play a crucial role in hemostasis. Sphingosine kinases (Sphk) 1 and 2 catalyze the conversion of sphingosine to the bioactive metabolite sphingosine 1-phosphate (S1P). Although platelets are able to secrete S1P on activation, little is known about a potential intrinsic effect of S1P on platelet function. Objective: To investigate the role of Sphk1- and Sphk2-derived S1P in the regulation of platelet function. Methods and Results: We found a 100-fold reduction in intracellular S1P levels in platelets derived from Sphk2 −/− mutants compared with Sphk1 −/− or wild-type mice, as analyzed by mass spectrometry. Sphk2 −/− platelets also failed to secrete S1P on stimulation. Blood from Sphk2-deficient mice showed decreased aggregation after protease-activated receptor 4-peptide and adenosine diphosphate stimulation in vitro, as assessed by whole blood impedance aggregometry. We revealed that S1P controls platelet aggregation via the sphingosine 1-phosphate receptor 1 through modulation of protease-activated receptor 4-peptide and adenosine diphosphate–induced platelet activation. Finally, we show by intravital microscopy that defective platelet aggregation in Sphk2-deficient mice translates into reduced arterial thrombus stability in vivo. Conclusions: We demonstrate that Sphk2 is the major Sphk isoform responsible for the generation of S1P in platelets and plays a pivotal intrinsic role in the control of platelet activation. Correspondingly, Sphk2-deficient mice are protected from arterial thrombosis after vascular injury, but have normal bleeding times. Targeting this pathway could therefore present a new therapeutic strategy to prevent thrombosis.

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Section: Sphk2-deficient Platelets Reveal Impaired Aggregationsupporting

confidence: 90%

Sphingosine 1-Phosphate Produced by Sphingosine Kinase 2 Intrinsically Controls Platelet Aggregation In Vitro and In Vivo

Urtz

Gaertner

Bruehl

et al. 2015

Circulation Research

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“…It is postulated that this exposure induces a procoagulant state that may help stem bleeding but may also cause a consumptive coagulopathy and secondary fibrinolysis that leads to delayed ICH. However, our data and those of others show that delayed bleeding often occurs in the absence of clinically relevant thrombocytopenia 49 or a clinically significant prolongation of clotting times, 3 suggesting that perturbations in other aspects of intracerebral hemostasis may predominate.…”

Section: Discussionsupporting

confidence: 51%

Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice

Hijazi¹,

Fanne²,

Abramovitch

et al. 2015

Blood

114

115

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“…48 and data not shown), P-selectin (49), or CD40-L (40). It is unlikely that the reduced platelet count in Nbeal2 -/-mice was responsible for their hemostatic and thrombotic defect, as we have recently shown that both hemostasis and thrombosis are largely unaffected by equivalent platelet count reductions in mice (50).…”

Section: Discussionmentioning

confidence: 93%

Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice

Deppermann¹,

Cherpokova²,

Nurden³

et al. 2013

J. Clin. Invest.

Self Cite

158

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Platelets are anuclear organelle-rich cell fragments derived from bone marrow megakaryocytes (MKs) that safeguard vascular integrity. The major platelet organelles, α-granules, release proteins that participate in thrombus formation and hemostasis. Proteins stored in α-granules are also thought to play a role in inflammation and wound healing, but their functional significance in vivo is unknown. Mutations in NBEAL2 have been linked to gray platelet syndrome (GPS), a rare bleeding disorder characterized by macrothrombocytopenia, with platelets lacking α-granules. Here we show that Nbeal2-knockout mice display the characteristics of human GPS, with defective α-granule biogenesis in MKs and their absence from platelets. Nbeal2 deficiency did not affect MK differentiation and proplatelet formation in vitro or platelet life span in vivo. Nbeal2-deficient platelets displayed impaired adhesion, aggregation, and coagulant activity ex vivo that translated into defective arterial thrombus formation and protection from thrombo-inflammatory brain infarction following focal cerebral ischemia. In a model of excisional skin wound repair, Nbeal2-deficient mice exhibited impaired development of functional granulation tissue due to severely reduced differentiation of myofibroblasts in the absence of α-granule secretion. This study demonstrates that platelet α-granule constituents are critically required not only for hemostasis but also thrombosis, acute thrombo-inflammatory disease states, and tissue reconstitution after injury.

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Only severe thrombocytopenia results in bleeding and defective thrombus formation in mice

Abstract: Key Points Hemostasis, thrombosis, and ischemic brain infarction efficiently occur at unexpectedly low platelet counts in mice. The threshold platelet count required for occlusive thrombus formation differs between thrombosis models.

Cited by 115 publications

References 51 publications

Sphingosine 1-Phosphate Produced by Sphingosine Kinase 2 Intrinsically Controls Platelet Aggregation In Vitro and In Vivo

Sphingosine 1-Phosphate Produced by Sphingosine Kinase 2 Intrinsically Controls Platelet Aggregation In Vitro and In Vivo

Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice

Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice

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