Characterization of a novel bleeding disorder with isolated prolonged bleeding time and deficiency of platelet microvesicle generation

Castaman, Giancarlo; Li, Yufeng; Battistin, Eliseo; Rodeghiero, Francesco

doi:10.1046/j.1365-2141.1997.d01-2072.x

Cited by 79 publications

(58 citation statements)

References 18 publications

(35 reference statements)

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“…Conversely, patients with an inherited bleeding disorder, Scott syndrome, develop severe hemorrhagic manifestations due to a defect in scramblase activity, leading to the lack of surface exposure of PS (thus resulting in an inadequate ability to promote a procoagulable state) and to the inability of platelets and other blood cells to generate MPs (59). Another bleeding disorder that results in a decreased capacity of platelets to shed MPs has also been described (60). In the same line of thought, our results showed that the levels of CD41a…”

Section: Discussionsupporting

confidence: 86%

Microparticles Provide a Novel Biomarker To Predict Severe Clinical Outcomes of Dengue Virus Infection

Punyadee

Mairiang

Thiemmeca

et al. 2015

J Virol

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Shedding of microparticles (MPs) is a consequence of apoptotic cell death and cellular activation. Low levels of circulating MPs in blood help maintain homeostasis, whereas increased MP generation is linked to many pathological conditions. Herein, we investigated the role of MPs in dengue virus (DENV) infection. Infection of various susceptible cells by DENV led to apoptotic death and MP release. These MPs harbored a viral envelope protein and a nonstructural protein 1 (NS1) on their surfaces. Ex vivo analysis of clinical specimens from patients with infections of different degrees of severity at multiple time points revealed that MPs generated from erythrocytes and platelets are two major MP populations in the circulation of DENV-infected patients. Elevated levels of red blood cell-derived MPs (RMPs) directly correlated with DENV disease severity, whereas a significant decrease in platelet-derived MPs was associated with a bleeding tendency. Removal by mononuclear cells of complement-opsonized NS1-anti-NS1 immune complexes bound to erythrocytes via complement receptor type 1 triggered MP shedding in vitro, a process that could explain the increased levels of RMPs in severe dengue. These findings point to the multiple roles of MPs in dengue pathogenesis. They offer a potential novel biomarker candidate capable of differentiating dengue fever from the more serious dengue hemorrhagic fever. IMPORTANCEDengue is the most important mosquito-transmitted viral disease in the world. No vaccines or specific treatments are available. Rapid diagnosis and immediate treatment are the keys to achieve a positive outcome. Dengue virus (DENV) infection, like some other medical conditions, changes the level and composition of microparticles (MPs), tiny bag-like structures which are normally present at low levels in the blood of healthy individuals. This study investigated how MPs in culture and patients' blood are changed in response to DENV infection. Infection of cells led to programmed cell death and MP release. In patients' blood, the majority of MPs originated from red blood cells and platelets. Decreased platelet-derived MPs were associated with a bleeding tendency, while increased levels of red blood cell-derived MPs (RMPs) correlated with more severe disease. Importantly, the level of RMPs during the early acute phase could serve as a biomarker to identify patients with potentially severe disease who require immediate care. E ach year, up to 390 million people are infected by dengue virus (DENV), the most significant mosquito-borne virus of the Flaviviridae family, posing serious socioeconomic and health burdens globally (1). Four serotypes of viruses (DENV serotype 1 [DENV-1], DENV-2, DENV-3, and DENV-4) are transmitted to humans by Aedes mosquitoes to establish both endemic and epidemic transmission cycles primarily in tropical and subtropical countries (1). Although the majority of DENV infections in humans are subclinical, a small fraction of infected individuals develops clinical symptoms ranging from a self-...

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Section: Discussionsupporting

confidence: 86%

Microparticles Provide a Novel Biomarker To Predict Severe Clinical Outcomes of Dengue Virus Infection

Punyadee

Mairiang

Thiemmeca

et al. 2015

J Virol

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“…43,44 Pedigree studies have shown that this defect equally affects males and females, consistent with an autosomal recessive inheritance pattern of the disorder. 42 To date, only 3 documented human cases of Scott syndrome have been reported. 42 The paucity of human cases has hindered genetic analyses of the trait.…”

Section: Membrane Remodeling and Microparticle Formation: Insights Frmentioning

confidence: 99%

“…42 To date, only 3 documented human cases of Scott syndrome have been reported. 42 The paucity of human cases has hindered genetic analyses of the trait. As the underlying defect seems to be the deficiency of phospholipid floppase, the initial candidate gene for Scott syndrome was the canonical phospholipid scramblase (PLSCR1).…”

Section: Membrane Remodeling and Microparticle Formation: Insights Frmentioning

confidence: 99%

Cellular Mechanisms Underlying the Formation of Circulating Microparticles

Morel

Jesel

Freyssinet

et al. 2011

ATVB

467

405

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Abstract-Microparticles (MPs) derived from platelets, monocytes, endothelial cells, red blood cells, and granulocytes may be detected in low concentrations in normal plasma and at increased levels in atherothrombotic cardiovascular diseases. The elucidation of the cellular mechanisms underlying the generation of circulating MPs is crucial for improving our understanding of their pathophysiological role in health and disease. The flopping of phosphatidylserine (PS) to the outer leaflet of the plasma membrane is the key event that will ultimately lead to the shedding of procoagulant MPs from activated or apoptotic cells. Research over the last few years has revealed important roles for calcium-, mitochondrial-, and caspase-dependent mechanisms leading to PS exposure. The study of Scott cells has unraveled different molecular mechanisms that may contribute to fine-tuning of PS exposure and MP release in response to a variety of specific stimuli. The pharmacological modulation of MP release may have a substantial therapeutic impact in the management of atherothrombotic vascular disorders. Because PS exposure is a key feature in pathological processes different from hemostasis and thrombosis, the most important obstacle in the field of MP-modulating drugs seems to be carefully targeting MP release to relevant cell types at an optimal level, so as to achieve a beneficial action and limit possible adverse effects. (Arterioscler Thromb Vasc Biol. 2011;31:15-26.)

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“…36 Serum aliquots were collected after 1, 2, and 7 hours of incubation (at 37°C) and immediately combined with 3.2% sodium citrate (1 vol citrate: 9 vol serum). For the PT assay, the citrate serum was added to a bovine fibrinogen solution (Sigma) containing a final concentration of fibrinogen of 1.5 mg/mL.…”

Section: Prothrombin Consumption Testmentioning

confidence: 99%

A hereditary bleeding disorder of dogs caused by a lack of platelet procoagulant activity

Brooks

Catalfamo

Brown

et al. 2002

Blood

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We have discovered a novel canine hereditary bleeding disorder with the characteristic features of Scott syndrome, a rare defect of platelet procoagulant activity. Affected dogs were from a single, inbred colony and experienced clinical signs of epistaxis, hyphema, intramuscular hematoma, and prolonged bleeding with cutaneous bruising after surgery. The hemostatic abnormalities identified were restricted to tests of platelet procoagulant activity, whereas platelet count, platelet morphology under light microscopy, bleeding time, clot retraction, and platelet aggregation and secretion in response to thrombin, collagen, and adenosine diphosphate stimulation were all within normal limits. Washed platelets from the affected dogs demonstrated approximately twice normal clotting times in a platelet factor 3 availability assay and, in a prothrombinase assay, generated only background levels of thrombin in response to calcium ionophore, thrombin, or combined thrombin plus collagen stimulation. While platelet phospholipid content was normal, flow cytometric analyses revealed diminished phosphatidylserine exposure and a failure of microvesiculation in response to calcium ionophore, thrombin, and collagen stimulation. Pedigree studies indicate a likely homozygous recessive inheritance pattern of the defect. These findings confirm the importance of platelet procoagulant activity for in vivo hemostasis and provide a large animal model for studying agonist-induced signal transduction, calcium mobilization, and effector pathways involved in the late platelet response of transmembrane phospholipid movement and membrane vesiculation. (Blood. 2002; 99:2434-2441)

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Characterization of a novel bleeding disorder with isolated prolonged bleeding time and deficiency of platelet microvesicle generation

Cited by 79 publications

References 18 publications

Microparticles Provide a Novel Biomarker To Predict Severe Clinical Outcomes of Dengue Virus Infection

Microparticles Provide a Novel Biomarker To Predict Severe Clinical Outcomes of Dengue Virus Infection

Cellular Mechanisms Underlying the Formation of Circulating Microparticles

A hereditary bleeding disorder of dogs caused by a lack of platelet procoagulant activity

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