Low adhesion receptor levels on circulating platelets in patients with lymphoproliferative diseases before receiving Navitoclax (ABT-263)

Qiao, Jian Lin; Schoenwaelder, Simone M.; Mason, Kylie D.; Tran, Huy; Davis, Amanda; Kaplan, Zane; Jackson, Shaun P.; Kile, Benjamin T.; Andrews, Robert K.; Roberts, Andrew W.; Gardiner, Elizabeth E.

doi:10.1182/blood-2012-12-467415

Cited by 21 publications

(19 citation statements)

References 10 publications

(3 reference statements)

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“…54 sGPVI levels are not elevated as a consequence of ablated platelet production. 55 We have investigated the utility of sGPVI as a marker of platelet activation in these pathological settings and explored the value of sGPVI to aid diagnosis and predict patient outcomes in conjunction with standard clinical parameters, including platelet count and injury severity scores. We have also investigated mechanisms that may drive release of sGPVI in trauma/inflammation patients.…”

Section: Discussionmentioning

confidence: 99%

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

Montague

Delierneux

Lecut³

et al. 2018

Blood Advances

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• Soluble GPVI is elevated in patients with thermal injury with sepsis, and sGPVI levels augment severity score prediction of mortality.• The GPVI ligand, fibrin, induces GPVI shedding without requirement for platelet activation or signaling Soluble glycoprotein VI (sGPVI) is shed from the platelet surface and is a marker of platelet activation in thrombotic conditions. We assessed sGPVI levels together with patient and clinical parameters in acute and chronic inflammatory conditions, including patients with thermal injury and inflammatory bowel disease and patients admitted to the intensive care unit (ICU)for elective cardiac surgery, trauma, acute brain injury, or prolonged ventilation. Plasma sGPVI was measured by enzyme-linked immunosorbent assay and was elevated on day 14 after thermal injury, and was higher in patients who developed sepsis. sGPVI levels were associated with sepsis, and the value for predicting sepsis was increased in combination with platelet count and Abbreviated Burn Severity Index. sGPVI levels positively correlated with levels of D-dimer (a fibrin degradation product) in ICU patients and patients with thermal injury. sGPVI levels in ICU patients at admission were significantly associated with 28-and 90-day mortality independent of platelet count. sGPVI levels in patients with thermal injury were associated with 28-day mortality at days 1, 14, and 21 when adjusting for platelet count. In both cohorts, sGPVI associations with mortality were stronger than D-dimer levels. Mechanistically, release of GPVI was triggered by exposure of platelets to polymerized fibrin, but not by engagement of G protein-coupled receptors by thrombin, adenosine 59-diphosphate, or thromboxane mimetics. Enhanced fibrin production in these patients may therefore contribute to the observed elevated sGPVI levels. sGPVI is an important platelet-specific marker for platelet activation that predicts sepsis progression and mortality in injured patients.

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Section: Discussionmentioning

confidence: 99%

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

Montague

Delierneux

Lecut³

et al. 2018

Blood Advances

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“…10 The concentration of ibrutinib required to inhibit 50% of collagen-inducedplatelet aggregation in PRP in our study approximates the peak concentration of the drug in humans. 6,13 Polymorphisms or drug interactions on ibrutinib metabolism leading to pharmacokinetics or pharmacodynamic variations as well as redundant platelet signaling pathways and variations in GPVI and GPIb expression in patients 19 may contribute to explain that only a subset of treated patients display spontaneous bleeding. The combined action of ibrutinib on GPVI and GPIb pathways likely explains the defect in primary hemostasis, particularly the bleeding in the microvasculature where the shear rate is elevated.…”

Section: Clinical Implicationmentioning

confidence: 99%

Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions

Levade

David

Garcia

et al. 2014

Blood

273

260

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Key Points• Ibrutinib affects collagen and VWF-mediated platelet activation.• The bleeding diathesis correlates with defects in collagen-induced platelet aggregation and firm adhesion on VWF at arterial shear rate.The oral Bruton's tyrosine kinase inhibitor, ibrutinib, has recently demonstrated high efficiency in patients with relapsed B-cell malignancies. Occurrence of bleeding events has been reported in a subgroup of ibrutinib-treated patients. We demonstrate that ibrutinib selectively inhibits platelet signaling and functions downstream of the collagen receptor glycoprotein VI and strongly affects firm platelet adhesion on von Willebrand factor (VWF) under arterial flow. A longitudinal study of 14 patients indicated a correlation between occurrence of bleeding events and decreased platelet aggregation in response to collagen in platelet-rich plasma and firm adhesion on VWF under arterial flow. The addition of 50% untreated platelets was sufficient to efficiently reverse the effects of ibrutinib, and platelet functions recovered after treatment interruption as physiological platelet renewal occurred. These data have important clinical implications and provide a basis for hemostasis management during ibrutinib treatment. (Blood. 2014;124(26):3991-3995) IntroductionThe Bruton tyrosine kinase (Btk) is an essential actor downstream of the B-cell receptor, and its covalent inhibitor, ibrutinib, has recently been approved for therapies of relapsed chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). [1][2][3][4][5][6][7][8] Bleeding has been reported in up to 50% of ibrutinib-treated patients. Most events were grade 1 to 2 (spontaneous bruising or petechiae), but in 5% of patients, they were of grade 3 or higher after trauma. [4][5][6] Platelets are the most important blood cells to prevent bleeding after vascular injury. Two Tec family kinases, Btk and Tec, are involved in platelet activation downstream of the collagen receptor glycoprotein VI (GPVI) via phospholipase Cg2 (PLCg2) phosphorylation and activation.9,10 Under arterial shear rate, interaction of platelets with the damaged vessel wall is largely mediated by binding of von Willebrand factor (VWF) to its receptor, the GPIb-IX-V complex. In a mouse model, Btk has been shown to play a role in VWF/GPIb-IX-V-induced platelet activation.11 To further characterize the bleeding events in ibrutinib-treated patients, we investigated the effect of this drug on platelet functions in vitro and ex vivo in 14 patients. Study designFor in vitro experiments, whole blood, platelet-rich plasma (PRP), or washed platelets from healthy donors free of antiplatelet medication were preincubated with ibrutinib (PCI-32765; Selleckchem) or dimethylsulfoxide for 10 or 30 minutes as indicated. For ex vivo experiments, blood samples were obtained before and 2 to 4 weeks after starting ibrutinib treatment (Imbruvica; Janssen-Cilaq Laboratories) in patients with CLL (420 mg daily) or MCL (560 mg daily) [4][5][6] (French compassionate use program) after informed consent, in ...

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“…Therapeutic concentrations of ibrutinib inhibit collagen/GPVIdependent platelet aggregation, 91 and although it is associated with clinical bleeding in patients with chronic lymphocytic leukemia, 91 this could be related to vulnerability resulting from decreased GPVI expression in lymphoproliferative disease. 92 Third, recent evidence that platelet Nox-1/2-dependent ROS production is important for GPIb-IX-V/GPVI-dependent platelet function, including adhesion to collagen, and is inhibited by Nox-1/2 inhibitors 19,20 raises the possibility that such inhibitors could be antithrombotic. An inhibitor targeting NOX1 and NOX4 (GKT137831) is in clinical trial as a treatment for diabetic nephropathy, 93 unrelated to any possible antiplatelet effects.…”

Section: Future Targets For Antiplatelet Therapymentioning

confidence: 99%

Current State and Novel Approaches of Antiplatelet Therapy

Metharom

Berndt

Baker

et al. 2015

ATVB

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Abstract-An unresolved problem with clinical use of antiplatelet therapy is that a significant number of individuals either still get thrombosis or run the risk of life-threatening bleeding. Antiplatelet drugs are widely used clinically, either chronically for people at risk of athero/thrombotic disease or to prevent thrombus formation during surgery. However, a subpopulation may be resistant to standard doses, while the platelet targets of these drugs are also critical for the normal hemostatic function of platelets. In this review, we will briefly examine current antiplatelet therapy and existing targets while focusing on new potential approaches for antiplatelet therapy and improved monitoring of effects on platelet reactivity in individuals, ultimately to improve antithrombosis with minimal bleeding. Primary platelet adhesion-signaling receptors, glycoprotein (

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Low adhesion receptor levels on circulating platelets in patients with lymphoproliferative diseases before receiving Navitoclax (ABT-263)

Cited by 21 publications

References 10 publications

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions

Current State and Novel Approaches of Antiplatelet Therapy

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