Inherited Defects in Platelet Signaling Mechanisms

Rao, A Koneti; Jalagadugula, Gauthami; Sun, Lisha

doi:10.1055/s-2004-835673

Cited by 59 publications

(26 citation statements)

References 69 publications

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“…The WAS protein is involved in reorganization of the actin cytoskeleton, which might be important for the proper localization of the specialized ER domains and other components involved in SOCE (4). Both syndromes are characterized by a combination of thrombocytopenia, small platelets, and a progressive decrease in T lymphocyte number and function, leading ultimately to immunodeficiency in WAS patients (41). This constellation suggests that alteration of SOCE might be involved in the pathophysiology of these and other syndromes, most notably idiopathic myelofibrosis, which resembles many of the alterations found in Stim1 Sax/+ mice (42).…”

Section: Discussionmentioning

confidence: 99%

An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice

Grosse¹,

Braun²,

et al. 2007

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Changes in cytoplasmic Ca 2+ levels regulate a variety of fundamental cellular functions in virtually all cells. In nonexcitable cells, a major pathway of Ca 2+ entry involves receptor-mediated depletion of intracellular Ca 2+ stores followed by the activation of store-operated calcium channels in the plasma membrane. We have established a mouse line expressing an activating EF hand motif mutant of stromal interaction molecule 1 (Stim1), an ER receptor recently identified as the Ca 2+ sensor responsible for activation of Ca 2+ releaseactivated (CRAC) channels in T cells, whose function in mammalian physiology is not well understood. Mice expressing mutant Stim1 had macrothrombocytopenia and an associated bleeding disorder. Basal intracellular Ca 2+ levels were increased in platelets, which resulted in a preactivation state, a selective unresponsiveness to immunoreceptor tyrosine activation motif-coupled agonists, and increased platelet consumption. In contrast, basal Ca 2+ levels, but not receptor-mediated responses, were affected in mutant T cells. These findings identify Stim1 as a central regulator of platelet function and suggest a cell type-specific activation or composition of the CRAC complex. IntroductionThe regulation of intracellular Ca 2+ ([Ca 2+ ] i ) is essentially involved in signaling processes in virtually all cells. In nonexcitable cells, including hematopoietic cells, Ca 2+ is released from the ER via inositol 1,4,5-triphosphate-mediated (IP 3 -mediated) receptor activation triggered by ligand-activated plasma membrane receptors. If the limited Ca 2+ reservoir of the ER becomes exhausted, extracellular Ca 2+ enters the cytoplasm by a mechanism known as store-operated Ca 2+ entry (SOCE) (1, 2). Although electrophysiologically well defined for more than a decade, the molecular identity of the pivotal proteins undoubtedly involved in SOCE has been discovered only recently. Stromal interaction molecule 1 (Stim1) is an ER resident protein necessary for the detection of ER Ca 2+ depletion (3-6). The 4-transmembrane domain protein Orai1, or CRACM, was reported recently to confer SOC activity (4,(7)(8)(9)(10)(11)(12). In T cells, Orai1 appears to be the predominant SOC (9), despite the fact that the C-terminal region of Stim1 has been shown to also interact with other SOC candidates such as transient receptor potential channels (TRPCs) 1,

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Section: Discussionmentioning

confidence: 99%

An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice

Grosse¹,

Braun²,

et al. 2007

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“…Some initial biochemical responses to agonist occupancy of non-G protein-linked receptors have also been defined (reviewed in Watson et al 142 and VargaSzabo et al 161 ). Specific second messengers and signaling proteins involved in inside-out signaling have been identified by biochemical studies of normal human platelets and megakaryocytes (reviewed in Shattil and Newman 141 ), genetic approaches in mice (reviewed in Lee and Blajchman 168 ), and studies of humans with rare inherited forms of platelet dysfunction (reviewed in Rao et al 171 ). Messengers include products of phospholipase C (IP 3 , which increases cytoplasmic free Ca 2ϩ ; diacylglycerol, which activates several protein kinase C isoforms in platelets as well as CalDAG-GEFI, a Rap1 GTPase exchange factor) and products of phosphatidylinositol 3-kinase (phosphatidylinositol 3,4 bisphosphate and phosphatidylinositol 3,4,5 trisphosphate, which recruit proteins with pleckstrin homology domains to membranes; reviewed in Brass 153 ).…”

Section: Inside-out Signalingmentioning

confidence: 99%

The GPIIb/IIIa (integrin αIIbβ3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend

Coller

Shattil

2008

Blood

314

342

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Starting 90 years ago with a clinical description by Glanzmann of a bleeding disorder associated with a defect in platelet function, technologic advances helped investigators identify the defect as a mutation(s) in the integrin family receptor, ␣IIb␤3, which has the capacity to bind fibrinogen (and other ligands) and support platelet-platelet interactions (aggregation). The receptor's activation state was found to be under exquisite control, with activators, inhibitors, and elaborate inside-out signaling mechanisms controlling its conformation. Structural biology has produced high-resolution images defining the ligand binding site at the atomic level. Research on ␣IIb␤3 has been bidirectional, with basic insights resulting in improved Glanzmann thrombasthenia carrier detection and prenatal diagnosis, assays to identify single nucleotide polymorphisms responsible for alloimmune neonatal thrombocytopenia, and the development of ␣IIb␤3 antagonists, the first rationally designed antiplatelet agents, to prevent and treat thrombotic cardiovascular disease. The future looks equally bright, with the potential for improved drugs and the application of gene therapy and stem cell biology to address the genetic abnormalities. The ␣IIb␤3 saga serves as a paradigm of rigorous science growing out of careful clinical observations of a rare disorder yielding both important new scientific information and improved diagnosis, therapy, and prevention of other disorders. (Blood. 2008;112: 3011-3025) Introduction"Thus blood, for all its raw physicality, its heat, color and smell, remains first and foremost a powerfully symbolic substancecapable of representing the most primeval forces of life, and of death." 1 "… for the blood is life …" Deuteronomy 12:23To celebrate the 50th anniversary of Blood, we offer an historical account of research on our favorite receptor on the platelet surface, GPIIb/IIIa, or integrin ␣IIb␤3. This receptor plays an important role in hemostasis and thrombosis, and in accord with the quotations above, both processes have profound effects on life and health. The origin of the English word blood is uncertain. It may derive from a postulated Indo-European root bhel, "bloom" or "sprout," and it has been speculated that "ancient people looked upon the effusion from incised skin as a sort of blooming," 2 an image well known to practitioners of the bleeding time.The dominant theme in this review is how improved understanding of the structure and function of ␣IIb␤3 has led to opportunities to translate that knowledge into biomedical advances, including the development of ␣IIb␤3 antagonists, the first class of rationally designed antiplatelet agents. The subtheme is how advances in scientific technology deriving from discoveries in other fields have been crucial to improving our understanding of ␣IIb␤3. Figure 1 is a timeline depicting, by category, approximately when different technologies were introduced into the investigation of blood platelets and/or ␣IIb␤3. Thus, as with a musical fugue, we will try to tell 2 sto...

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“…A diagnosis of primary platelet function disorder was made if the patient had not taken any drugs known to affect platelet function for at least 10 days before investigation, had normal platelet counts, an abnormal (but not absent) platelet aggregation to standard platelet agonists (adenosine 59-diphosphate [ADP], arachidonic acid, collagen), an abnormal (but not absent) agglutination to ristocetin, and a positive bleeding history. 22 Platelet aggregation abnormalities had to be confirmed in a blood sample drawn at a later time point.…”

Section: Patientsmentioning

confidence: 99%

The effect of desmopressin on platelet function: a selective enhancement of procoagulant COAT platelets in patients with primary platelet function defects

Colucci

Stutz

Rochat

et al. 2014

Blood

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Key Points• DDAVP is the drug of choice for mild hemophilia A and von Willebrand disease and (by unclear mechanisms) for platelet function disorders.• In vivo DDAVP selectively and markedly enhances the ability to form procoagulant platelets by enhancing intracellular Na 1 and Ca 21 fluxes.is clinically efficacious in patients with mild platelet function disorders but it is not known which mechanisms mediate this effect. Our aim was to evaluate the impact of in vivo DDAVP administration in these patients. We assessed von Willebrand factor (VWF), factor VIII, platelet activation and aggregation, platelet-dependent thrombin generation, and platelet intracellular Na 1 /Ca 21 fluxes, before and 2 and 4 hours after DDAVP (0.3 mg/kg). We found (1) no significant changes for P-selectin expression, PAC-1 binding, d-granule content and secretion, and platelet-aggregation; (2) significant decreases of secretion of a-granules and GPIIb-IIIa activation induced by adenosine 59-diphosphate, convulxin, and thrombin; (3) significant increases of procoagulant platelets induced by convulxin/thrombin and platelet-dependent thrombin generation; and (4) significant increases of intracellular Na 1 /Ca 21 concentrations. We show that in vivo DDAVP selectively and markedly enhances the ability to form procoagulant platelets and increases platelet-dependent thrombin generation by enhancing Na

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Inherited Defects in Platelet Signaling Mechanisms

Cited by 59 publications

References 69 publications

An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice

An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice

The GPIIb/IIIa (integrin αIIbβ3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend

The effect of desmopressin on platelet function: a selective enhancement of procoagulant COAT platelets in patients with primary platelet function defects

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