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 ...
Host defense against infection is based on two crucial mechanisms: the inflammatory response and the activation of coagulation. Platelets are involved in both hemostasis and immune response. These mechanisms work together in a complex and synchronous manner making the contribution of platelets of major importance in sepsis. This is a summary of the pathophysiology of sepsis-induced thrombocytopenia, microvascular consequences, platelet-endothelial cells and platelet–pathogens interactions. The critical role of platelets during sepsis and the therapeutic implications are also reviewed.
Dasatinib is an oral potent adenosine triphosphate (ATP)-competitive inhibitor of BCR-ABL, cKIT, platelet-derived growth factor receptor, and SRC family kinases (SFKs), which has demonstrated high efficiency in patients with imatinib-resistant chronic myelogenous leukemia. Here, we show that dasatinib weakly affects platelet activation by thrombin or adenosine diphosphate but is a potent inhibitor of platelet signaling and functions initiated by collagen or Fc␥RIIA cross-linking, which require immunoreceptor tyrosinebased activation motif phosphorylation by SFKs. Accordingly, dasatinib treatment rapidly decreases the volume of thrombi formed under arterial flow conditions in whole blood from patients or mice perfused over a matrix of collagen. Moreover, treatment of mice with dasatinib increases the tail bleeding time in a dose-dependent manner. Interestingly, these effects are rapidly reversible after interruption of the treatment. Our data clearly demonstrate that, in contrast to imatinib, dasatinib affects platelet functions in vitro and in vivo, which has important implications in clinic and could explain increased risks of bleeding observed in patients. Moreover, dasatinib efficiently prevents platelet activation mediated by Fc␥RIIA cross-linking and by sera from patients with heparin-induced thrombocytopenia, suggesting that reversible antiplatelet agents acting as ATP-competitive inhibitors of SFKs may be of therapeutic interest in the treatment of this pathology.
The novel Corona virus infection (Covid-19) first identified in China in December 2019 has rapidly progressed in pandemic leading to significant mortality and unprecedented challenge for healthcare systems. Although the clinical spectrum of Covid-19 is variable, acute respiratory failure and systemic coagulopathy are common in severe Covid-19 patients. Lung is an important target of the SARS-CoV-2 virus causing eventually acute respiratory distress syndrome associated to a thromboinflammatory state. The cytokinic storm, thromboinflammation and pulmonary tropism are the bedrock of tissue lesions responsible for acute respiratory failure and for prolonged infection that may lead to multiple organ failure and death. The thrombogenicity of this infectious disease is illustrated by the high frequency of thromboembolic events observed even in Covid-19 patients treated with anticoagulation. Increased D-Dimers, a biomarker reflecting activation of hemostasis and fibrinolysis, and low platelet count (thrombocytopenia) are associated with higher mortality in Covid-19 patients. In this review, we will summarize our current knowledge on the thromboembolic manifestations, the disturbed hemostatic parameters, and the thromboinflammatory conditions associated to Covid-19 and we will discuss the modalities of anticoagulant treatment or other potential antithrombotic options.
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