Publications by authors named "Alec A Schmaier"

20 Publications

  • Page 1 of 1

Vasculopathy in COVID-19.

Blood 2022 Jan 5. Epub 2022 Jan 5.

Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States.

COVID-19 is a primary respiratory illness that is frequently complicated by systemic involvement of the vasculature. Vascular involvement leads to an array of complications ranging from thrombosis to pulmonary edema secondary to loss of barrier function. This review will address the vasculopathy of COVID-19 with a focus on the role of the endothelium in orchestrating the systemic response to SARS-CoV-2 infection. The endothelial receptor systems and molecular pathways activated in the setting of COVID-19 and the consequences of these inflammatory and prothrombotic changes on endothelial cell function will be discussed. The sequelae of COVID-19 vascular involvement at the level of organ systems will also be addressed, with an emphasis on the pulmonary vasculature, but with consideration of effects on other vascular beds. The dramatic changes in endothelial phenotypes associated with COVID-19 has enabled the identification of biomarkers that could help guide therapy and predict outcomes. Knowledge of vascular pathogenesis in COVID-19 has also informed therapeutic approaches that may control its systemic sequelae. Since our understanding of vascular response in COVID-19 continues to evolve, we will consider areas of controversy, such as the extent to which SARS-CoV-2 directly infects endothelium and the degree to which vascular responses to SARS-CoV-2 are unique or common to those of other viruses capable of causing severe respiratory disease. This conceptual framework describing how SARS-CoV-2 infection affects endothelial inflammation, prothrombotic transformation, and barrier dysfunction will provide a context for interpreting new information as it arises addressing the vascular complications of COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021012250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8736280PMC
January 2022

Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights into Cardiovascular Disease.

Circulation 2021 Nov 24. Epub 2021 Nov 24.

Department of Exercise Science, University of South Carolina, Columbia, SC.

Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Proteomic profiling of 1,301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥ 5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study. We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8 × 10. These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β = 0.61±0.05, p-value = 3.27 × 10) and MMP-3 (β = -0.60±0.05, p = 1.67 × 10), as well as a completely novel pleiotropic locus at the gene, associated with nine proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1 associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β = 0.34±0.04, p = 1.34 × 10) as well as an association between ATTR amyloidosis and RBP4 levels in community dwelling individuals without heart failure. Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation and myocardial function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055117DOI Listing
November 2021

Venous Thromboembolism for the Practicing Cardiologist.

Cardiol Clin 2021 Nov;39(4):551-566

Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 4th Floor, 375 Longwood Avenue, Boston, MA 02215, USA. Electronic address:

Venous thromboembolism (VTE), encompassing pulmonary embolism (PE) and deep vein thrombosis (DVT), is encountered commonly. Acute PE may present as a high-risk cardiovascular emergency, and acute DVT can cause acute and chronic vascular complications. The goal of this review is to ensure that cardiologists are comfortable managing VTE-including risk stratification, anticoagulation therapy, and familiarity with primary reperfusion therapy. Clinical assessment and determination of degree of right ventricular dysfunction are critical in initial risk stratification of PE and determination of parenteral versus oral anticoagulation therapy. Direct oral anticoagulants have emerged as preferred first-line oral anticoagulation strategy in VTE scenarios.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccl.2021.06.008DOI Listing
November 2021

Nicotinamide Adenine Dinucleotide Biosynthetic Impairment and Urinary Metabolomic Alterations Observed in Hospitalized Adults With COVID-19-Related Acute Kidney Injury.

Kidney Int Rep 2021 Dec 14;6(12):3002-3013. Epub 2021 Sep 14.

Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.

Introduction: Acute kidney injury (AKI) is common in COVID-19 and associated with increased morbidity and mortality. We investigated alterations in the urine metabolome to test the hypothesis that impaired nicotinamide adenine dinucleotide (NAD) biosynthesis and other deficiencies in energy metabolism in the kidney, previously characterized in ischemic, toxic, and inflammatory etiologies of AKI, will be present in COVID-19-associated AKI.

Methods: This is a case-control study among the following 2 independent populations of adults hospitalized with COVID-19: a critically ill population in Boston, Massachusetts, and a general population in Birmingham, Alabama. The cases had AKI stages 2 or 3 by Kidney Disease Improving Global Outcomes (KDIGO) criteria; the controls had no AKI. Metabolites were measured by liquid chromatography-mass spectrometry.

Results: A total of 14 cases and 14 controls were included from Boston and 8 cases and 10 controls from Birmingham. Increased urinary quinolinate-to-tryptophan ratio (Q/T), found with impaired NAD biosynthesis, was present in the cases at each location and pooled across locations (median [interquartile range]: 1.34 [0.59-2.96] in cases, 0.31 [0.13-1.63] in controls,  = 0.0013). Altered energy metabolism and purine metabolism contributed to a distinct urinary metabolomic signature that differentiated patients with and without AKI (supervised random forest class error: 2 of 28 in Boston, 0 of 18 in Birmingham).

Conclusion: Urinary metabolites spanning multiple biochemical pathways differentiate AKI versus non-AKI in patients hospitalized with COVID-19 and suggest a conserved impairment in NAD biosynthesis, which may present a novel therapeutic target to mitigate COVID-19-associated AKI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ekir.2021.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439094PMC
December 2021

Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19.

JCI Insight 2021 10 22;6(20). Epub 2021 Oct 22.

Division of Nephrology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.

Endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. Constitutively, the endothelial surface is anticoagulant, a property maintained at least in part via signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant endothelial dysfunction and alterations in the Tie2/angiopoietin axis. Primary HUVECs treated with plasma from patients with severe COVID-19 upregulated the expression of thromboinflammatory genes, inhibited the expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. Lung autopsies from patients with COVID-19 demonstrated a prothrombotic endothelial signature. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity, and the highest levels were associated with worse survival. These data highlight the disruption of Tie2/angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19. Our findings provide rationale for current trials of Tie2-activating therapy with AKB-9778 in COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.151527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564889PMC
October 2021

Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19.

medRxiv 2021 May 17. Epub 2021 May 17.

Profound endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. In the quiescent state, the endothelial surface is anticoagulant, a property maintained at least in part via constitutive signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from activated endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant dysfunction of the endothelium and alterations in the Tie2-angiopoietin axis. Primary human endothelial cells treated with plasma from patients with severe COVID-19 upregulated the expression of thromboinflammatory genes, inhibited expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. On lung autopsy specimens from COVID-19 patients, we found a prothrombotic endothelial signature as evidenced by increased von Willebrand Factor and loss of anticoagulant proteins. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed profound endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity and highest levels were associated with worse survival. These data highlight the disruption of Tie2-angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19. Moreover, our findings provide novel rationale for current trials of Tie2 activating therapy with AKB-9778 in severe COVID-19 disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.05.13.21257070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142666PMC
May 2021

Vascular Disease Patient Information Page: COVID-19-related thrombosis.

Vasc Med 2020 12 12;25(6):604-607. Epub 2020 Oct 12.

Division of Hematology and Oncology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1358863X20963804DOI Listing
December 2020

A Lack of Reserve: Recognizing the Large Impact of Small Vessels in the Heart.

Circulation 2018 07 23;138(4):424-428. Epub 2018 Jul 23.

Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School, Boston, Massachusetts.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.117.031602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287614PMC
July 2018

Venous Thromboembolism and Cancer.

Curr Cardiol Rep 2018 08 20;20(10):89. Epub 2018 Aug 20.

Brigham & Women's Hospital, 75 Francis St. AB378, Boston, MA, 02115, USA.

Purpose Of Review: This review aims to summarize the epidemiology, current pathophysiologic understanding, and state-of-the-art treatment of venous thromboembolism (VTE) in cancer patients.

Recent Findings: The risk of VTE varies among cancer patients. Recently introduced prediction models better identify those at high risk of VTE. New mechanisms underlying hypercoagulability in cancer have been uncovered. Initial data on the efficacy of direct oral anticoagulants (DOACs) compared with low-molecular weight heparin to treat VTE in patients with cancer are promising. However, they may be associated with higher risk of gastrointestinal bleeding. VTE causes significant morbidity and mortality in cancer patients. Our understanding of the mechanisms of VTE, including those associated with cancer treatments, has significantly grown. The assessment of the benefit/risk balance of VTE treatment remains challenging in many patients with cancer. The introduction of DOACs has expanded treatment options, but knowledge on their efficacy and safety is incomplete.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11886-018-1034-3DOI Listing
August 2018

Are Patients Getting Their Aspirin's Worth in Ischemic Stroke?

J Am Heart Assoc 2018 06 1;7(11). Epub 2018 Jun 1.

Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.118.009564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015345PMC
June 2018

Human platelets as a platform to monitor metabolic biomarkers using stable isotopes and LC-MS.

Bioanalysis 2013 Dec;5(24):3009-21

Department of Pharmacology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.

Background: Intracellular metabolites such as CoA thioesters are modulated in a number of clinical settings. Their accurate measurement from surrogate tissues such as platelets may provide additional information to current serum and urinary biomarkers.

Methods: Freshly isolated platelets from healthy volunteers were treated with rotenone, propionate or isotopically labeled metabolic tracers. Using a recently developed LC-MS-based methodology, absolute changes in short-chain acyl-CoA thioesters were monitored, as well as relative metabolic labeling using isotopomer distribution analysis.

Results: Consistent with in vitro experiments, isolated platelets treated with rotenone showed decreased intracellular succinyl-CoA and increased β-hydroxybutyryl-CoA, while propionate treatment resulted in increased propionyl-CoA. In addition, isotopomers of the CoAs were readily detected in platelets treated with the [(13)C]- or [(13)C(15)N]-labeled metabolic precursors.

Conclusion: Here, we show that human platelets can provide a powerful ex vivo challenge platform with potential clinical diagnostic and biomarker discovery applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4155/bio.13.269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3912754PMC
December 2013

Angiotensin 1-7 and Mas decrease thrombosis in Bdkrb2-/- mice by increasing NO and prostacyclin to reduce platelet spreading and glycoprotein VI activation.

Blood 2013 Apr 5;121(15):3023-32. Epub 2013 Feb 5.

Hematology and Oncology Division, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.

Bradykinin B2 receptor-deleted mice (Bdkrb2(-/-)) have delayed carotid artery thrombosis times and prolonged tail bleeding time resulting from elevated angiotensin II (AngII) and angiotensin receptor 2 (AT2R) producing increased plasma nitric oxide (NO) and prostacyclin. Bdkrb2(-/-) also have elevated plasma angiotensin-(1-7) and messenger RNA and protein for its receptor Mas. Blockade of Mas with its antagonist A-779 in Bdkrb2(-/-) shortens thrombosis times (58 ± 4 minutes to 38 ± 4 minutes) and bleeding times (170 ± 13 seconds to 88 ± 8 seconds) and lowers plasma nitrate (22 ± 4 μM to 15 ± 5 μM), and 6-keto-PGF1α (259 ± 103 pg/mL to 132 ± 58 pg/mL). Bdkrb2(-/-) platelets express increased NO, guanosine 3',5'-cyclic monophosphate, and cyclic adenosine monophosphate with reduced spreading on collagen, collagen peptide GFOGER, or fibrinogen. In vivo A-779 or combined L-NAME and nimesulide treatment corrects it. Bdkrb2(-/-) platelets have reduced collagen-related peptide-induced integrin α2bβ3 activation and P-selectin expression that are partially corrected by in vivo A-779, nimesulide, or L-NAME. Bone marrow transplantations show that the platelet phenotype and thrombosis time depends on the host rather than donor bone marrow progenitors. Transplantation of wild-type bone marrow into Bdkrb2(-/-) hosts produces platelets with a spreading defect and delayed thrombosis times. In Bdkrb2(-/-), combined AT2R and Mas overexpression produce elevated plasma prostacyclin and NO leading to acquired platelet function defects and thrombosis delay.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2012-09-459156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3624945PMC
April 2013

Occlusive thrombi arise in mammals but not birds in response to arterial injury: evolutionary insight into human cardiovascular disease.

Blood 2011 Sep 3;118(13):3661-9. Epub 2011 Aug 3.

Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Mammalian platelets are small, anuclear circulating cells that form tightly adherent, shear-resistant thrombi to prevent blood loss after vessel injury. Platelet thrombi that form in coronary and carotid arteries also underlie common vascular diseases such as myocardial infarction and stroke and are the target of drugs used to treat these diseases. Birds have high-pressure cardiovascular systems like mammals but generate nucleated thrombocytes rather than platelets. Here, we show that avian thrombocytes respond to many of the same activating stimuli as mammalian platelets but are unable to form shear-resistant aggregates ex vivo. Avian thrombocytes are larger than mammalian platelets, spread less efficiently on collagen, and express much lower levels of the α(₂b)β₃ integrin required for aggregate formation, features predicted to make thrombocyte aggregates less resistant than platelets are to the high fluid shear forces of the arterial vasculature. In vivo carotid vessel injury stimulates the formation of occlusive platelet thrombi in mice but not in the size- and flow-matched carotid artery of the Australian budgerigar. These studies indicate that unique physical and molecular features of mammalian platelets enable them to form shear-resistant arterial thrombi, an essential element in the pathogenesis of human cardiovascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2011-02-338244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186337PMC
September 2011

MicroRNA expression in maturing murine megakaryocytes.

Blood 2010 Dec 18;116(23):e128-38. Epub 2010 Aug 18.

Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

MicroRNAs are small noncoding RNAs that regulate cellular development by interfering with mRNA stability and translation. We examined global microRNA expression during the differentiation of murine hematopoietic progenitors into megakaryocytes. Of 435 miRNAs analyzed, 13 were up-regulated and 81 were down-regulated. Many of these changes are consistent with miRNA profiling studies of human megakaryocytes and platelets, although new patterns also emerged. Among 7 conserved miRNAs that were up-regulated most strongly in murine megakaryocytes, 6 were also induced in the related erythroid lineage. MiR-146a was strongly up-regulated during mouse and human megakaryopoiesis but not erythropoiesis. However, overexpression of miR-146a in mouse bone marrow hematopoietic progenitor populations produced no detectable alterations in megakaryocyte development or platelet production in vivo or in colony assays. Our findings extend the repertoire of differentially regulated miRNAs during murine megakaryopoiesis and provide a useful new dataset for hematopoiesis research. In addition, we show that enforced hematopoietic expression of miR-146a has minimal effects on megakaryopoiesis. These results are compatible with prior studies indicating that miR-146a inhibits megakaryocyte production indirectly by suppressing inflammatory cytokine production from innate immune cells, but cast doubt on a different study, which suggests that this miRNA inhibits megakaryopoiesis cell-autonomously.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2010-06-292920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012601PMC
December 2010

Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling.

Blood 2010 Jul 2;116(4):661-70. Epub 2010 Apr 2.

Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd., Philadelphia, PA 19104, USA.

Although platelets appear by embryonic day 10.5 in the developing mouse, an embryonic role for these cells has not been identified. The SYK-SLP-76 signaling pathway is required in blood cells to regulate embryonic blood-lymphatic vascular separation, but the cell type and molecular mechanism underlying this regulatory pathway are not known. In the present study we demonstrate that platelets regulate lymphatic vascular development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2 (CLEC-2) receptors. PODOPLANIN (PDPN), a transmembrane protein expressed on the surface of lymphatic endothelial cells, is required in nonhematopoietic cells for blood-lymphatic separation. Genetic loss of the PDPN receptor CLEC-2 ablates PDPN binding by platelets and confers embryonic lymphatic vascular defects like those seen in animals lacking PDPN or SLP-76. Platelet factor 4-Cre-mediated deletion of Slp-76 is sufficient to confer lymphatic vascular defects, identifying platelets as the cell type in which SLP-76 signaling is required to regulate lymphatic vascular development. Consistent with these genetic findings, we observe SLP-76-dependent platelet aggregate formation on the surface of lymphatic endothelial cells in vivo and ex vivo. These studies identify a nonhemostatic pathway in which platelet CLEC-2 receptors bind lymphatic endothelial PDPN and activate SLP-76 signaling to regulate embryonic vascular development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2010-02-270876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324297PMC
July 2010

Molecular priming of Lyn by GPVI enables an immune receptor to adopt a hemostatic role.

Proc Natl Acad Sci U S A 2009 Dec 25;106(50):21167-72. Epub 2009 Nov 25.

Department of Medicine, Division of Cardiology, Division of Hematology, Institute for Medicine and Engineering, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

The immune receptor signaling pathway is used by nonimmune cells, but the molecular adaptations that underlie its functional diversification are not known. Circulating platelets use the immune receptor homologue glycoprotein VI (GPVI) to respond to collagen exposed at sites of vessel injury. In contrast to immune cell responses, platelet activation must take place within seconds to successfully form thrombi in flowing blood. Here, we show that the GPVI receptor utilizes a unique intracellular proline-rich domain (PRD) to accelerate platelet activation, a requirement for efficient platelet adhesion to collagen under flow. The GPVI PRD specifically binds the Src-family kinase Lyn and directly activates it, presumably through SH3 displacement. In resting platelets, Lyn is constitutively bound to GPVI in an activated state and platelets lacking Lyn exhibit defective collagen adhesion like that of platelets with GPVI receptors lacking the PRD. These findings define a molecular priming mechanism that enables an immune-type receptor to adopt a hemostatic function. These studies also demonstrate that active kinases can constitutively associate with immune-type receptors without initiating signal transduction before receptor ligation, consistent with a recent molecular model of immune receptor signaling in which receptor ligation is required to bring active kinases to their receptor substrates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0906436106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2795544PMC
December 2009

Platelet integrin signaling: wherefore art thou?

Blood 2009 Sep;114(13):2571-2

UNIVERSITY OF PENNSYLVANIA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2009-08-235283DOI Listing
September 2009

Thrombosis in flowing blood.

Blood 2009 Jul;114(4):754-6

University of Pennsylvania; Case Western Reserve University, PA, USA.

In this issue of Blood, van der Meijden and colleagues report on the mechanisms by which collagen exposure in flow-dependent circulation contributes to thrombus formation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2009-05-218107DOI Listing
July 2009

Negative regulation of activated alpha-2 integrins during thrombopoiesis.

Blood 2009 Jun 3;113(25):6428-39. Epub 2009 Mar 3.

Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, 19104, USA.

Circulating platelets exhibit rapid signaling and adhesive responses to collagen that facilitate hemostasis at sites of vessel injury. Because platelets are anuclear, their collagen receptors must be expressed by megakaryocytes, platelet precursors that arise in the collagen-rich environment of the bone marrow. Whether and how megakaryocytes regulate collagen adhesion during their development in the bone marrow are unknown. We find that surface expression of activated, but not wild-type, alpha2 integrins in hematopoietic cells in vivo results in the generation of platelets that lack surface alpha2 receptors. Culture of hematopoietic progenitor cells ex vivo reveals that surface levels of activated, but not wild-type, alpha2 integrin receptors are rapidly down-regulated during cell growth on collagen but reach wild-type levels when cells are grown in the absence of collagen. Progenitor cells that express activated alpha2 integrins are normally distributed in the bone marrow in vivo and exhibit normal migration across a collagen-coated membrane ex vivo. This migration is accompanied by rapid down-regulation of activated surface integrins. These studies identify ligand-dependent removal of activated alpha2 receptors from the cell surface as a mechanism by which integrin function can be negatively regulated in hematopoietic cells during migration between the adhesive environment of the bone marrow and the nonadhesive environment of the circulating blood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2008-08-175356DOI Listing
June 2009

Structure-function analysis reveals discrete beta3 integrin inside-out and outside-in signaling pathways in platelets.

Blood 2007 Apr 14;109(8):3284-90. Epub 2006 Dec 14.

Division of Cardiology and Department of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104, USA.

A unique aspect of integrin receptor function is the transmission of bidirectional signals. In platelets alphaIIbbeta3 integrins require "inside-out" signals to bind fibrinogen and form thrombi. Following ligand binding, alphaIIbbeta3 integrins generate "outside-in" signals that contribute to thrombus stability. Because integrin cytoplasmic tails are short and lack enzymatic activity, bidirectional signals are believed to be mediated by interactions with intracellular proteins, but the molecular basis for integrin signal transduction remains poorly understood. In the present study we have used retroviral vectors to express alphaIIbbeta3 integrins with mutant beta3 tails in mouse platelets and test mechanisms of bidirectional signaling. Using this approach we identify mutations (eg, beta3Y747A) that confer loss of signaling in both directions and others (eg, beta3T762A) that confer a selective loss of outside-in signals. These results reveal the presence of discrete bidirectional signaling pathways controlled by integrin beta subunits in platelets and describe a high-throughput means of further investigating these pathways in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2006-10-051664DOI Listing
April 2007
-->