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Is SARS-COV2 Hijacking the Complement and Coagulation Systems?

Posted in Biomarkers: Inflammation, Coagulation Therapy and Internal Bleeding, Coronavirus Gene Expression, COVID-19, COVID-19 effects on Human Heart, number of asymptomatic infections, Platelet count disorder, Population Health Management, SAR-Cov-2 a vasculotropic (blood vessels) RNA Virus, SARS-CoV-2, SARS-COV2 Hijacking the Complement and Coagulation Systems, Serology tests for coronavirus antibodies, Treatment Protocols for COVID-19, Virus Infective Acute Respiratory Syndrome: SARS-CoV, tagged , , , , , , , , on August 4, 2020| Leave a Comment »

Is SARS-COV2 Hijacking the Complement and Coagulation Systems?

Reporter: Stephen J. Williams, PhD

In a recent Nature Medicine paper “Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection” Ramlall et al. demonstrate, in a retrospective study, that a significant number of patients presenting SARS-CoV2 complications had prior incidences of macular degeneration and coagulation disorders and these previous indications are risk factors for COVID-related complications.

 

Abstract

Understanding the pathophysiology of SARS-CoV-2 infection is critical for therapeutic and public health strategies. Viral–host interactions can guide discovery of disease regulators, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of coronaviruses. To determine whether conditions associated with dysregulated complement or coagulation systems impact disease, we performed a retrospective observational study and found that history of macular degeneration (a proxy for complement-activation disorders) and history of coagulation disorders (thrombocytopenia, thrombosis and hemorrhage) are risk factors for SARS-CoV-2-associated morbidity and mortality—effects that are independent of age, sex or history of smoking. Transcriptional profiling of nasopharyngeal swabs demonstrated that in addition to type-I interferon and interleukin-6-dependent inflammatory responses, infection results in robust engagement of the complement and coagulation pathways. Finally, in a candidate-driven genetic association study of severe SARS-CoV-2 disease, we identified putative complement and coagulation-associated loci including missense, eQTL and sQTL variants of critical complement and coagulation regulators. In addition to providing evidence that complement function modulates SARS-CoV-2 infection outcome, the data point to putative transcriptional genetic markers of susceptibility. The results highlight the value of using a multimodal analytical approach to reveal determinants and predictors of immunity, susceptibility and clinical outcome associated with infection.

Introduction

As part of a separate study, the authors mapped over 140 cellular proteins that are structurally mimicked by coronaviruses (CoVs) and identified complement and coagulation pathways as targets of this strategy across all CoV strains4. The complement system is a critical defense against pathogens, including viruses5 and when dysregulated (by germline variants or acquired through age-related effects or excessive tissue damage) can contribute to pathologies mediated by inflammation5,6,7.

“So, virally encoded structural mimics of complement and coagulation factors may contribute to CoV-associated immune-mediated pathology and indicate sensitivities in antiviral defenses.”

 

Methods and Results

  • Between 1 February 2020 and 25 April 2020, 11,116 patients presented to New York-Presbyterian/Columbia University Irving Medical Center with suspected SARS-CoV-2 infection, of which 6,398 tested positive
  • Electronic health records (EHRs) were used to define sex, age and smoking history status as well as histories of macular degeneration, coagulatory disorders (thrombocytopenia, thrombosis and hemorrhage), hypertension, type 2 diabetes (T2D), coronary artery disease (CAD) and obesity (see Methods). A Python algorithm was used to analyze all confounders.
  • identified 88 patients with history of macular degeneration, 4 with complement deficiency disorders and 1,179 with coagulatory disorders).
  • observed a 35% mortality rate among patients that were put on mechanical ventilation and that 31% of deceased patients had been on mechanical respiration.
  • patients with AMD (a proxy for complement activation disorders) and coagulation disorders (thrombocytopenia, thrombosis and hemorrhage) were at significantly increased risk of adverse clinical outcomes (including mechanical respiration and death) following SARS-CoV-2 infection
  • 650 NP swabs from control and SARS-CoV-2-infected patients who presented to Weill-Cornell Medical Center were evaluated by RNA-Seq. Gene set enrichment analysis (GSEA) of Hallmark gene sets found that SARS-CoV-2 infection (as defined by presence of SARS-CoV-2 RNA and stratified into ‘positive’, ‘low’, ‘medium’ or ‘high’ based on viral load; induces genes related to pathways with known immune modulatory functions (Fig. 2a). Moreover, among the most enriched gene sets, SARS-CoV-2 infection induces robust activation of the complement cascade (false discovery rate (FDR) P < 0.001), with increasing enrichment and significance with viral load (FDR P < 0.0001).
  • KEGG Pathway Analysis revealed KEGG_Complement_and_Coagulation_Cascades’, ‘GO_Coagulation’ and ‘Reactome_initial_triggering_of_complement’ to be significantly enriched in expression profiles of SARS-CoV-2-infected samples
  • conducted a candidate-driven study to evaluate whether genetic variation within a 60-Kb window around 102 genes with known roles in regulating complement or coagulation cascades (2,888 genetic variants fulfill this criteria of the 805,426 profiled in the UK Biobank) is associated with poor SARS-CoV-2 clinical outcome
  • identified 11 loci representing seven genes with study-wide significance. A variant of coagulation factor III (F3), variant rs72729504, was found to be associated with increased risk of adverse clinical outcome associated with SARS-CoV-2 infection. The analysis also identified that four variants previously reported to be associated with AMD (rs45574833, rs61821114, rs61821041 and rs12064775)15predispose carriers to hospitalization following SARS-CoV-2 infection

As authors state:

“Among the implications, the data warrant heightened public health awareness for the most vulnerable individuals and further investigation into an existing menu of complement and coagulation targeting therapies that were recently shown to be beneficial in a small cohort of patients with SARS-CoV-2 infection.” 26,27.

 

References

Ramlall, V., Thangaraj, P.M., Meydan, C. et al. Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection. Nat Med (2020). https://doi.org/10.1038/s41591-020-1021-2

 

4.

Lasso, G., Honig, B. & Shapira, S. D. A sweep of earth’s virome reveals host-guided viral protein structural mimicry; with implications for human disease. Preprint at bioRxiv https://doi.org/10.1101/2020.06.18.159467 (2020).

 

SUMMARY

Viruses deploy an array of genetically encoded strategies to coopt host machinery and support viral replicative cycles. Molecular mimicry, manifested by structural similarity between viral and endogenous host proteins, allow viruses to harness or disrupt cellular functions including nucleic acid metabolism and modulation of immune responses. Here, we use protein structure similarity to scan for virally encoded structure mimics across thousands of catalogued viruses and hosts spanning broad ecological niches and taxonomic range, including bacteria, plants and fungi, invertebrates and vertebrates. Our survey identified over 6,000,000 instances of structural mimicry, the vast majority of which (>70%) cannot be discerned through protein sequence. The results point to molecular mimicry as a pervasive strategy employed by viruses and indicate that the protein structure space used by a given virus is dictated by the host proteome. Interrogation of proteins mimicked by human-infecting viruses points to broad diversification of cellular pathways targeted via structural mimicry, identifies biological processes that may underly autoimmune disorders, and reveals virally encoded mimics that may be leveraged to engineer synthetic metabolic circuits or may serve as targets for therapeutics. Moreover, the manner and degree to which viruses exploit molecular mimicry varies by genome size and nucleic acid type, with ssRNA viruses circumventing limitations of their small genomes by mimicking human proteins to a greater extent than their large dsDNA counterparts. Finally, we identified over 140 cellular proteins that are mimicked by CoV, providing clues about cellular processes driving the pathogenesis of the ongoing COVID-19 pandemic.

 

26.

Risitano, A. M. Complement as a target in COVID-19?. Nat. Rev. Immunol. 20, 343–344 (2020).

 

27.

Mastaglio, S. et al. The first case of COVID-19 treated with the complement C3 inhibitor AMY-101. Clin. Immunol. 215, 108450 (2020).

 

28.

Polubriaginof, F. C. G. et al. Challenges with quality of race and ethnicity data in observational databases. J. Am. Med. Inf. Assoc. 26, 730–736 (2019).

 

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Mechanism of Platelet Granule Release and its Role in Thrombus Formation: Lead Contributor to discoveries, Robert Flaumenhaft, MD, PhD, Division of Hemostasis and Thrombosis at BIDMC and Harvard Medical School

Posted in Coagulation Therapy and Internal Bleeding, Interviews with Scientific Leaders on May 1, 2019| Leave a Comment »

Mechanism of Platelet Granule Release and its Role in Thrombus Formation: Lead Contributor to discoveries, Robert Flaumenhaft, MD, PhD, Division of Hemostasis and Thrombosis at BIDMC and Harvard Medical School

Reporter: Aviva Lev-Ari, PhD, RN

Article ID #265: Mechanism of Platelet Granule Release and its Role in Thrombus Formation: Lead Contributor to discoveries, Robert Flaumenhaft, MD, PhD, Division of Hemostasis and Thrombosis at BIDMC and Harvard Medical School. Published on 5/1/2019

WordCloud Image Produced by Adam Tubman

 

It is well known that platelets are crucial for stopping bleeding. Platelets prevent excessive posttraumatic blood loss at sites of vascular injury by forming a platelet plug. Upon exposure of the subendothelial extracellular matrix, platelets are recruited to the site of injury and become activated, resulting in firm adhesion and subsequent platelet aggregation. The molecular mechanisms underlying the formation of a hemostatic platelet plug are relatively well understood: upon exposure of the subendothelial matrix, platelets either interact directly with matrix proteins (eg, via glycoprotein VI [GPVI] and α2β1 to collagen) or bind to von Willebrand factor (VWF) that is deposited at the site of injury. Transient interactions between platelet GPIb and VWF support platelet tethering at sites of high shear stress. Firm adhesion and subsequent aggregation is mediated by activated integrin receptors such as αIIbβ3. G-protein–coupled receptors mediate activation signals after being triggered by soluble agonists such as thrombin, thromboxane A2, and adenosine 5′-diphosphate, which reinforce thrombus propagation.

SOURCE

Simon F. De Meyer
Blood 2017 129:1573-1574; doi: https://doi.org/10.1182/blood-2017-02-763540

http://www.bloodjournal.org/content/129/12/1573?sso-checked=true

To address the role of platelet granule content in maintaining vascular integrity in inflammation, Deppermann et al generated Unc13d−/−/Nbeal2−/− mice.1 Platelets from these mice are unable to secrete their α- or dense-granule content. The authors used these mice in models of lung inflammation, skin inflammation, and brain infarction. Similar to previous studies, intradermal hemorrhage was observed in platelet-depleted wild-type (WT) mice at the site of inflammation. Strikingly, no bleeding was observed in the inflamed skin of Unc13d−/−/Nbeal2−/− mice. Analogous results were observed in lung inflammation. These experiments show that release of α or dense granules is not necessary to maintain vascular integrity at sites of acute inflammation in skin and lung. Much different results were however obtained in the stroke model used by the authors. Indeed, when subjected to transient middle cerebral artery occlusion, Unc13d−/−/Nbeal2−/− mice were prone to intracranial bleeding in the infarcted areas. Cerebral hemorrhage in these mice resulted in a significantly increased mortality compared with WT animals. In an elegant approach using platelet transfusion experiments, the authors showed that the observed effects of combined Munc13-4 and Nbeal deficiency were related to the platelet-specific secretion effects and not to potential defects in other cells.

SOURCE

Simon F. De Meyer
Blood 2017 129:1573-1574; doi: https://doi.org/10.1182/blood-2017-02-763540

http://www.bloodjournal.org/content/129/12/1573?sso-checked=true

 

Procoagulant platelets: generation, function, and therapeutic targeting in thrombosis

Ejaife O. Agbani and Alastair W. Poole
Blood 2017 130:2171-2179; doi: https://doi.org/10.1182/blood-2017-05-787259

Abstract

Current understanding of how platelets localize coagulation to wound sites has come mainly from studies of a subpopulation of activated platelets. In this review, we summarize data from the last 4 decades that have described these platelets with a range of descriptive titles and attributes. We identify striking overlaps in the reported characteristics of these platelets, which imply a single subpopulation of versatile platelets and thus suggest that their commonality requires unification of their description. We therefore propose the term procoagulant platelet as the unifying terminology. We discuss the agonist requirements and molecular drivers for the dramatic morphological transformation platelets undergo when becoming procoagulant. Finally, we provide perspectives on the biomarker potential of procoagulant platelets for thrombotic events as well as on the possible clinical benefits of inhibitors of carbonic anhydrase enzymes and the water channel Aquaporin-1 for targeting this subpopulation of platelets as antiprocoagulant antithrombotics.

SOURCE

http://www.bloodjournal.org/content/130/20/2171

Robert Flaumenhaft, MD, PhD – A Biography

https://www.bidmc.org/research/research-by-department/medicine/hemostasis-and-thrombosis/flaumenhaft-lab/biography

Most cited
 2009 Jul;23(4):177-89. doi: 10.1016/j.blre.2009.04.001. Epub 2009 May 17.

Platelet alpha-granules: basic biology and clinical correlates.

Blair P1, Flaumenhaft R.

Abstract

alpha-Granules are essential to normal platelet activity. These unusual secretory granules derive their cargo from both regulated secretory and endocytotic pathways in megakaryocytes. Rare, inheritable defects of alpha-granule formation in mice and man have enabled identification of proteins that mediate cargo trafficking and alpha-granule formation. In platelets, alpha-granules fuse with the plasma membrane upon activation, releasing their cargo and increasing platelet surface area. The mechanisms that control alpha-granule membrane fusion have begun to be elucidated at the molecular level. SNAREs and SNARE accessory proteins that control alpha-granule secretion have been identified. Proteomic studies demonstrate that hundreds of bioactive proteins are released from alpha-granules. This breadth of proteins implies a versatile functionality. While initially known primarily for their participation in thrombosis and hemostasis, the role of alpha-granules in inflammation, atherosclerosis, antimicrobial host defense, wound healing, angiogenesis, and malignancy has become increasingly appreciated as the function of platelets in the pathophysiology of these processes has been defined. This review will consider the formation, release, and physiologic roles of alpha-granules with special emphasis on work performed over the last decade.

PMID:
19450911
PMCID:
PMC2720568
DOI:
10.1016/j.blre.2009.04.001

SOURCE

https://www.ncbi.nlm.nih.gov/pubmed/19450911

 

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    Translation:HumansAnimalsCells

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    Translation:HumansAnimalsCells

  • Jain A, Barrile R, van der Meer AD, Mammoto A, Mammoto T, De Ceunynck K, Aisiku O, Otieno MA, Louden CS, Hamilton GA, Flaumenhaft R, Ingber DE. Primary Human Lung Alveolus-on-a-chip Model of Intravascular Thrombosis for Assessment of Therapeutics. Clin Pharmacol Ther. 2018 02; 103(2):332-340. PMID: 28516446.

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  • Flaumenhaft R, De Ceunynck K. Targeting PAR1: Now What? Trends Pharmacol Sci. 2017 08; 38(8):701-716. PMID: 28558960.

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    Translation:HumansAnimals

  • Stopa JD, Baker KM, Grover SP, Flaumenhaft R, Furie B. Kinetic-based trapping by intervening sequence variants of the active sites of protein-disulfide isomerase identifies platelet protein substrates. J Biol Chem. 2017 06 02; 292(22):9063-9074. PMID: 28364042.

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  • Schiemer J, Bohm A, Lin L, Merrill-Skoloff G, Flaumenhaft R, Huang JS, Le Breton GC, Chishti AH. Ga13 Switch Region 2 Relieves Talin Autoinhibition to Activate aIIbß3 Integrin. J Biol Chem. 2016 Dec 23; 291(52):26598-26612. PMID: 27803165.

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    Translation:HumansAnimalsCells

  • Flaumenhaft R. Young platelets out-of-control. Thromb Haemost. 2016 10 28; 116(5):780. PMID: 27683761.

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    Translation:HumansCells

  • Atefi G, Aisiku O, Shapiro N, Hauser C, Dalle Lucca J, Flaumenhaft R, Tsokos GC. Complement Activation in Trauma Patients Alters Platelet Function. Shock. 2016 09; 46(3 Suppl 1):83-8. PMID: 27355402.

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    Translation:HumansCells

  • Bekendam RH, Bendapudi PK, Lin L, Nag PP, Pu J, Kennedy DR, Feldenzer A, Chiu J, Cook KM, Furie B, Huang M, Hogg PJ, Flaumenhaft R. A substrate-driven allosteric switch that enhances PDI catalytic activity. Nat Commun. 2016 08 30; 7:12579.PMID: 27573496.

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    Translation:HumansAnimalsCells

  • Flaumenhaft R. SERCAmnavigating calcium signaling in platelets. Blood. 2016 08 25; 128(8):1034-5. PMID: 27563149.

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  • Flaumenhaft R, Furie B. Vascular thiol isomerases. Blood. 2016 08 18; 128(7):893-901. PMID: 27357699.

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    Translation:HumansAnimalsCells

  • Gong L, Proulle V, Fang C, Hong Z, Lin Z, Liu M, Xue G, Yuan C, Lin L, Furie B, Flaumenhaft R, Andreasen P, Furie B, Huang M. A specific plasminogen activator inhibitor-1 antagonist derived from inactivated urokinase. J Cell Mol Med. 2016 10; 20(10):1851-60. PMID: 27197780.

    Citations: 1  

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    Translation:HumansAnimalsCells

  • Bekendam RH, Flaumenhaft R. Inhibition of Protein Disulfide Isomerase in Thrombosis. Basic Clin Pharmacol Toxicol. 2016 Oct; 119 Suppl 3:42-48. PMID: 26919268.

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    Translation:HumansAnimalsCells

  • Flaumenhaft R. Probing for thiol isomerase activity in thrombi. J Thromb Haemost. 2016 05; 14(5):1067-9. PMID: 26854753.

    Fields:

    Translation:Humans

  • Jain A, Graveline A, Waterhouse A, Vernet A, Flaumenhaft R, Ingber DE. A shear gradient-activated microfluidic device for automated monitoring of whole blood haemostasis and platelet function. Nat Commun. 2016 Jan 06; 7:10176. PMID: 26733371.

    Citations: 13  

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    Translation:HumansAnimalsCells

  • Schulman S, Bendapudi P, Sharda A, Chen V, Bellido-Martin L, Jasuja R, Furie BC, Flaumenhaft R, Furie B. Extracellular Thiol Isomerases and Their Role in Thrombus Formation. Antioxid Redox Signal. 2016 Jan 01; 24(1):1-15. PMID: 26467859.

    Citations: 10  

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    Translation:HumansAnimalsCells

  • Lin L, Gopal S, Sharda A, Passam F, Bowley SR, Stopa J, Xue G, Yuan C, Furie BC, Flaumenhaft R, Huang M, Furie B. Quercetin-3-rutinoside Inhibits Protein Disulfide Isomerase by Binding to Its b’x Domain. J Biol Chem. 2015 Sep 25; 290(39):23543-52. PMID: 26240139.

    Citations: 11   Fields:

    Translation:HumansAnimalsCells

  • Flaumenhaft R. A new story ARC for a-granule formation. Blood. 2015 Jul 09; 126(2):123-4. PMID: 26160182.

    Citations: 

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    Translation:HumansAnimalsCells

  • Koseoglu S, Peters CG, Fitch-Tewfik JL, Aisiku O, Danglot L, Galli T, Flaumenhaft R. VAMP-7 links granule exocytosis to actin reorganization during platelet activation. Blood. 2015 Jul 30; 126(5):651-60. PMID: 25999457.

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    Translation:HumansAnimalsCells

  • Sakurai Y, Fitch-Tewfik JL, Qiu Y, Ahn B, Myers DR, Tran R, Fay ME, Ding L, Spearman PW, Michelson AD, Flaumenhaft R, Lam WA. Platelet geometry sensing spatially regulates a-granule secretion to enable matrix self-deposition. Blood. 2015 Jul 23; 126(4):531-8. PMID: 25964667.

    Citations: 2   Fields:

    Translation:HumansCells

  • Sharda A, Kim SH, Jasuja R, Gopal S, Flaumenhaft R, Furie BC, Furie B. Defective PDI release from platelets and endothelial cells impairs thrombus formation in Hermansky-Pudlak syndrome. Blood. 2015 Mar 05; 125(10):1633-42. PMID: 25593336.

    Citations: 16   Fields:

    Translation:HumansAnimalsCells

  • Aisiku O, Peters CG, De Ceunynck K, Ghosh CC, Dilks JR, Fustolo-Gunnink SF, Huang M, Dockendorff C, Parikh SM, Flaumenhaft R. Parmodulins inhibit thrombus formation without inducing endothelial injury caused by vorapaxar. Blood. 2015 Mar 19; 125(12):1976-85. PMID: 25587041.

    Citations: 11   Fields:

    Translation:HumansAnimalsCells

  • Flaumenhaft R. Making (anti)sense of factor XI in thrombosis. N Engl J Med. 2015 Jan 15; 372(3):277-8. PMID: 25482334.

    Citations: 1  

    27 readers on Mendeley

    Translation:Humans

  • Flaumenhaft R. Thrombus formation reimagined. Blood. 2014 Sep 11; 124(11):1697-8. PMID: 25214193.

    Citations: 2   Fields:

    Translation:HumansAnimals

  • Flaumenhaft R, Furie B, Zwicker JI. Therapeutic implications of protein disulfide isomerase inhibition in thrombotic disease. Arterioscler Thromb Vasc Biol. 2015 Jan; 35(1):16-23. PMID: 25104801.

    Citations: 19  

    25 readers on Mendeley

    Translation:HumansAnimalsCells

  • Furie B, Flaumenhaft R. Thiol isomerases in thrombus formation. Circ Res. 2014 Mar 28; 114(7):1162-73. PMID: 24677236.

    Citations: 23  

    41 readers on Mendeley

     

    Translation:HumansAnimalsCells

  • Flaumenhaft R. Bioengineering in platelet biology. Thromb Res. 2014 Apr; 133(4):523-4. PMID: 24433610.

    Fields:

    Translation:HumansAnimalsCells

  • Battinelli EM, Markens BA, Kulenthirarajan RA, Machlus KR, Flaumenhaft R, Italiano JE. Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response. Blood. 2014 Jan 02; 123(1):101-12. PMID: 24065244.

    Citations: 26   Fields:

    Translation:HumansCells

  • Koseoglu S, Flaumenhaft R. Advances in platelet granule biology. Curr Opin Hematol. 2013 Sep; 20(5):464-71. PMID: 23839294.

    Citations: 19  

    40 readers on Mendeley

     

    Translation:HumansCells

  • Fitch-Tewfik JL, Flaumenhaft R. Platelet granule exocytosis: a comparison with chromaffin cells. Front Endocrinol (Lausanne). 2013; 4:77. PMID: 23805129.

    Citations: 9  

    65 readers on Mendeley

     

  • Flaumenhaft R. Protein disulfide isomerase as an antithrombotic target. Trends Cardiovasc Med. 2013 Oct; 23(7):264-8. PMID: 23541171.

    Citations: 10  

    20 readers on Mendeley

     

    Translation:HumansAnimalsCells

  • Koseoglu S, Dilks JR, Peters CG, Fitch-Tewfik JL, Fadel NA, Jasuja R, Italiano JE, Haynes CL, Flaumenhaft R. Dynamin-related protein-1 controls fusion pore dynamics during platelet granule exocytosis. Arterioscler Thromb Vasc Biol. 2013 Mar; 33(3):481-8. PMID: 23288151.

    Citations: 12  

    36 readers on Mendeley

     

    Translation:HumansAnimalsCells

  • Flaumenhaft R. a-granules: a story in the making. Blood. 2012 Dec 13; 120(25):4908-9. PMID: 23243155.

    Citations: 1  

    23 readers on Mendeley

    Translation:HumansCells

  • Flaumenhaft R. Monitoring granule traffic in megakaryocytes. Blood. 2012 Nov 08; 120(19):3869-70. PMID: 23144159.

    Fields:

    Translation:HumansCells

  • Thon JN, Peters CG, Machlus KR, Aslam R, Rowley J, Macleod H, Devine MT, Fuchs TA, Weyrich AS, Semple JW, Flaumenhaft R, Italiano JE. T granules in human platelets function in TLR9 organization and signaling. J Cell Biol. 2012 Aug 20; 198(4):561-74. PMID: 22908309.

    Citations: 36  

    82 readers on Mendeley

     

    Translation:HumansAnimalsCells

  • Peters CG, Michelson AD, Flaumenhaft R. Granule exocytosis is required for platelet spreading: differential sorting of a-granules expressing VAMP-7. Blood. 2012 Jul 05; 120(1):199-206. PMID: 22589474.

    Citations: 23   Fields:

    Translation:HumansAnimalsCells

  • Jasuja R, Passam FH, Kennedy DR, Kim SH, van Hessem L, Lin L, Bowley SR, Joshi SS, Dilks JR, Furie B, Furie BC, Flaumenhaft R. Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents. J Clin Invest. 2012 Jun; 122(6):2104-13. PMID: 22565308.

    Citations: 57  

    90 readers on Mendeley

     

    Translation:HumansAnimalsCells

  • Ashitate Y, Kim SH, Tanaka E, Henary M, Choi HS, Frangioni JV, Flaumenhaft R. Two-wavelength near-infrared fluorescence for the quantitation of drug antiplatelet effects in large animal model systems. J Vasc Surg. 2012 Jul; 56(1):171-80. PMID: 22503225.

    Citations: 9   Fields:

    Translation:HumansAnimalsCells

  • Dockendorff C, Aisiku O, Verplank L, Dilks JR, Smith DA, Gunnink SF, Dowal L, Negri J, Palmer M, Macpherson L, Schreiber SL, Flaumenhaft R. Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor. ACS Med Chem Lett. 2012 Mar 08; 3(3):232-237. PMID: 22408714.

    Citations: 10  

    27 readers on Mendeley

     

  • Flaumenhaft R. Platelets get the message. Blood. 2011 Aug 18; 118(7):1712-3. PMID: 21852441.

    Citations: 1  

    17 readers on Mendeley

     

  • Dowal L, Yang W, Freeman MR, Steen H, Flaumenhaft R. Proteomic analysis of palmitoylated platelet proteins. Blood. 2011 Sep 29; 118(13):e62-73. PMID: 21813449.

    Citations: 34   Fields:

    Translation:HumansCells

  • Nachtigall MJ, Jessel RH, Flaumenhaft R, Nachtigall R, Yoles I, Naftolin F, Nachtigall LE. The selective estrogen receptor modulator DT56a (Femarelle) does not affect platelet reactivity in normal or thrombophilic postmenopausal women. Menopause. 2011 Mar; 18(3):285-8. PMID: 21037489.

    Citations: 1   Fields:

    Translation:HumansCells

  • Dowal L, Sim DS, Dilks JR, Blair P, Beaudry S, Denker BM, Koukos G, Kuliopulos A, Flaumenhaft R. Identification of an antithrombotic allosteric modulator that acts through helix 8 of PAR1. Proc Natl Acad Sci U S A. 2011 Feb 15; 108(7):2951-6.PMID: 21282664.

    Citations: 25   Fields:

    Translation:AnimalsCells

  • Liu J, Gao BB, Clermont AC, Blair P, Chilcote TJ, Sinha S, Flaumenhaft R, Feener EP. Hyperglycemia-induced cerebral hematoma expansion is mediated by plasma kallikrein. Nat Med. 2011 Feb; 17(2):206-10. PMID: 21258336.

    Citations: 38  

    68 readers on Mendeley

    Translation:Animals

  • Flaumenhaft R. Filling a void in Gray Platelets. Blood. 2010 Dec 02; 116(23):4738-40. PMID: 21127182.

    Citations: 1   Fields:

  • Flaumenhaft R, Mairuhu AT, Italiano JE. Platelet- and megakaryocyte-derived microparticles. Semin Thromb Hemost. 2010 Nov; 36(8):881-7. PMID: 21049389.

    Citations: 10   Fields:

    Translation:HumansCells

  • Italiano JE, Mairuhu AT, Flaumenhaft R. Clinical relevance of microparticles from platelets and megakaryocytes. Curr Opin Hematol. 2010 Nov; 17(6):578-84. PMID: 20739880.

    Citations: 56   Fields:

    Translation:HumansAnimalsCells

  • Woronowicz K, Dilks JR, Rozenvayn N, Dowal L, Blair PS, Peters CG, Woronowicz L, Flaumenhaft R. The platelet actin cytoskeleton associates with SNAREs and participates in alpha-granule secretion. Biochemistry. 2010 Jun 01; 49(21):4533-42.PMID: 20429610.

    Citations: 17   Fields:

    Translation:HumansCells

  • Dowal L, Flaumenhaft R. Targeting platelet G-protein coupled receptors (GPCRs): looking beyond conventional GPCR antagonism. Curr Vasc Pharmacol. 2010 Mar; 8(2):140-54. PMID: 19485898.

    Citations: 8   Fields:

    Translation:HumansAnimalsCells

  • Flaumenhaft R. Getting in shape with RanBP10. Blood. 2009 Dec 24; 114(27):5412-3. PMID: 20035043.

    Citations: 1   Fields:

  • Tanaka E, Chen FY, Flaumenhaft R, Graham GJ, Laurence RG, Frangioni JV. Real-time assessment of cardiac perfusion, coronary angiography, and acute intravascular thrombi using dual-channel near-infrared fluorescence imaging. J Thorac Cardiovasc Surg. 2009 Jul; 138(1):133-40. PMID: 19577070.

    Citations: 24  

    26 readers on Mendeley

    Translation:Animals

  • Blair P, Flaumenhaft R. Platelet alpha-granules: basic biology and clinical correlates. Blood Rev. 2009 Jul; 23(4):177-89. PMID: 19450911.

    Citations: 144  

    352 readers on Mendeley
    2 readers on CiteULike

     

    Translation:HumansAnimalsCells

  • Graham GJ, Ren Q, Dilks JR, Blair P, Whiteheart SW, Flaumenhaft R. Endobrevin/VAMP-8-dependent dense granule release mediates thrombus formation in vivo. Blood. 2009 Jul 30; 114(5):1083-90. PMID: 19395672.

    Citations: 34   Fields:

    Translation:HumansAnimalsCells

  • Flaumenhaft R, Nachtigall M, Lowenstein J, Nachtigall L, Nachtigall R, Nachtigall L. Association of oral but not transdermal estrogen therapy with enhanced platelet reactivity in a subset of postmenopausal women. Menopause. 2009 Mar-Apr; 16(2):407-12. PMID: 18989235.

    Citations: 2   Fields:

    Translation:HumansCells

  • Flaumenhaft R, Dilks JR, Richardson J, Alden E, Patel-Hett SR, Battinelli E, Klement GL, Sola-Visner M, Italiano JE. Megakaryocyte-derived microparticles: direct visualization and distinction from platelet-derived microparticles. Blood. 2009 Jan 29; 113(5):1112-21. PMID: 18802008.

    Citations: 52  

    129 readers on Mendeley

    Translation:HumansAnimalsCells

  • Flaumenhaft R, Dilks JR. Discovery-based strategies for studying platelet function. Mini Rev Med Chem. 2008 Apr; 8(4):350-7.PMID: 18473926.

    Citations: 2   Fields:

    Translation:HumansCells

  • Dilks JR, Flaumenhaft R. Fluoxetine (Prozac) augments platelet activation mediated through protease-activated receptors. J Thromb Haemost. 2008 Apr; 6(4):705-8. PMID: 18194419.

    Citations: 3   Fields:

    Translation:HumansCells

  • Flaumenhaft R, Rozenvayn N, Feng D, Dvorak AM. SNAP-23 and syntaxin-2 localize to the extracellular surface of the platelet plasma membrane. Blood. 2007 Sep 01; 110(5):1492-501. PMID: 17485553.

    Citations: 5  

    38 readers on Mendeley

     

    Translation:HumansCellsCT

  • Sim DS, Dilks JR, Flaumenhaft R. Platelets possess and require an active protein palmitoylation pathway for agonist-mediated activation and in vivo thrombus formation. Arterioscler Thromb Vasc Biol. 2007 Jun; 27(6):1478-85. PMID: 17303775.

    Citations: 12  

    24 readers on Mendeley

    Translation:HumansAnimalsCells

  • Flaumenhaft R, Tanaka E, Graham GJ, De Grand AM, Laurence RG, Hoshino K, Hajjar RJ, Frangioni JV. Localization and quantification of platelet-rich thrombi in large blood vessels with near-infrared fluorescence imaging. Circulation. 2007 Jan 02; 115(1):84-93. PMID: 17179017.

    Citations: 15  

    30 readers on Mendeley

     

    Translation:HumansAnimalsCells

  • Flaumenhaft R. Formation and fate of platelet microparticles. Blood Cells Mol Dis. 2006 Mar-Apr; 36(2):182-7. PMID: 16466949.

    Citations: 32   Fields:

    Translation:HumansCells

  • Flaumenhaft R, Lo EH. Different strokes for rodent folks. Nat Methods. 2006 Feb; 3(2):79-80. PMID: 16432514.

    Citations: 1   Fields:

    Translation:Animals

  • Flaumenhaft R, Sim DS. Protein palmitoylation in signal transduction of hematopoietic cells. Hematology. 2005 Dec; 10(6):511-9.PMID: 16321817.

    Citations: 2   Fields:

    Translation:HumansAnimalsCells

  • O’Connell DJ, Rozenvayn N, Flaumenhaft R. Phosphatidylinositol 4,5-bisphosphate regulates activation-induced platelet microparticle formation. Biochemistry. 2005 Apr 26; 44(16):6361-70. PMID: 15835925.

    Citations: 5   Fields:

    Translation:HumansCells

  • Sim D, Flaumenhaft R, Furie B, Furie B. Interactions of platelets, blood-borne tissue factor, and fibrin during arteriolar thrombus formation in vivo. Microcirculation. 2005 Apr-May; 12(3):301-11. PMID: 15814438.

    Citations: 9   Fields:

    Translation:HumansAnimalsCells

  • Flaumenhaft R, Dilks JR, Rozenvayn N, Monahan-Earley RA, Feng D, Dvorak AM. The actin cytoskeleton differentially regulates platelet alpha-granule and dense-granule secretion. Blood. 2005 May 15; 105(10):3879-87. PMID: 15671445.

    Citations: 29   Fields:

    Translation:HumansCells

  • Falati S, Gross PL, Merrill-Skoloff G, Sim D, Flaumenhaft R, Celi A, Furie BC, Furie B. In vivo models of platelet function and thrombosis: study of real-time thrombus formation. Methods Mol Biol. 2004; 272:187-97. PMID: 15226545.

    Citations: 12   Fields:

    Translation:AnimalsCells

  • Flaumenhaft R. Platelet permeabilization. Methods Mol Biol. 2004; 273:365-78. PMID: 15308812.

    Citations: 1   Fields:

    Translation:HumansCells

  • Sim DS, Merrill-Skoloff G, Furie BC, Furie B, Flaumenhaft R. Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels. Blood. 2004 Mar 15; 103(6):2127-34. PMID: 14645013.

    Citations: 20   Fields:

    Translation:HumansAnimalsCells

  • Flaumenhaft R, Sim DS. The platelet as a model for chemical genetics. Chem Biol. 2003 Jun; 10(6):481-6. PMID: 12837380.

    Citations: 2   Fields:

    Translation:HumansAnimalsCells

  • Flaumenhaft R. Molecular basis of platelet granule secretion. Arterioscler Thromb Vasc Biol. 2003 Jul 01; 23(7):1152-60. PMID: 12738684.

    Citations: 30   Fields:

    Translation:Cells

  • Lai KC, Flaumenhaft R. SNARE protein degradation upon platelet activation: calpain cleaves SNAP-23. J Cell Physiol. 2003 Feb; 194(2):206-14. PMID: 12494459.

    Citations: 5   Fields:

    Translation:HumansCells

  • Celi A, Merrill-Skoloff G, Gross P, Falati S, Sim DS, Flaumenhaft R, Furie BC, Furie B. Thrombus formation: direct real-time observation and digital analysis of thrombus assembly in a living mouse by confocal and widefield intravital microscopy. J Thromb Haemost. 2003 Jan; 1(1):60-8. PMID: 12871540.

    Citations: 25   Fields:

    Translation:AnimalsCells

  • Rozenvayn N, Flaumenhaft R. Protein kinase C mediates translocation of type II phosphatidylinositol 5-phosphate 4-kinase required for platelet alpha-granule secretion. J Biol Chem. 2003 Mar 07; 278(10):8126-34. PMID: 12509423.

    Citations: 8  

    17 readers on Mendeley

    Translation:HumansCells

  • Feng D, Crane K, Rozenvayn N, Dvorak AM, Flaumenhaft R. Subcellular distribution of 3 functional platelet SNARE proteins: human cellubrevin, SNAP-23, and syntaxin 2. Blood. 2002 Jun 01; 99(11):4006-14. PMID: 12010801.

    Citations: 24   Fields:

    Translation:HumansCells

  • Furie B, Furie BC, Flaumenhaft R. A journey with platelet P-selectin: the molecular basis of granule secretion, signalling and cell adhesion. Thromb Haemost. 2001 Jul; 86(1):214-21. PMID: 11487009.

    Citations: 33   Fields:

    Translation:HumansCells

  • Rozenvayn N, Flaumenhaft R. Phosphatidylinositol 4,5-bisphosphate mediates Ca2+-induced platelet alpha-granule secretion: evidence for type II phosphatidylinositol 5-phosphate 4-kinase function. J Biol Chem. 2001 Jun 22; 276(25):22410-9. PMID: 11304526.

    Citations: 6   Fields:

    Translation:HumansCells

  • Feng D, Flaumenhaft R, Bandeira-Melo C, Weller P, Dvorak A. Ultrastructural localization of vesicle-associated membrane protein(s) to specialized membrane structures in human pericytes, vascular smooth muscle cells, endothelial cells, neutrophils, and eosinophils. J Histochem Cytochem. 2001 Mar; 49(3):293-304. PMID: 11181732.

    Citations: 12   Fields:

    Translation:HumansCells

  • Yang J, Hirata T, Croce K, Merrill-Skoloff G, Tchernychev B, Williams E, Flaumenhaft R, Furie BC, Furie B. Targeted gene disruption demonstrates that P-selectin glycoprotein ligand 1 (PSGL-1) is required for P-selectin-mediated but not E-selectin-mediated neutrophil rolling and migration. J Exp Med. 1999 Dec 20; 190(12):1769-82. PMID: 10601352.

    Citations: 70  

    53 readers on Mendeley

     

    Translation:AnimalsCells

  • Croce K, Flaumenhaft R, Rivers M, Furie B, Furie BC, Herman IM, Potter DA. Inhibition of calpain blocks platelet secretion, aggregation, and spreading. J Biol Chem. 1999 Dec 17; 274(51):36321-7. PMID: 10593923.

    Citations: 22   Fields:

    Translation:HumansCells

  • Flaumenhaft R, Furie B, Furie BC. Alpha-granule secretion from alpha-toxin permeabilized, MgATP-exposed platelets is induced independently by H+ and Ca2+. J Cell Physiol. 1999 Apr; 179(1):1-10. PMID: 10082126.

    Citations: 4   Fields:

    Translation:HumansCells

  • Flaumenhaft R, Croce K, Chen E, Furie B, Furie BC. Proteins of the exocytotic core complex mediate platelet alpha-granule secretion. Roles of vesicle-associated membrane protein, SNAP-23, and syntaxin 4. J Biol Chem. 1999 Jan 22; 274(4):2492-501. PMID: 9891020.

    Citations: 31   Fields:

    Translation:HumansCells

  • Thorpe CM, Flaumenhaft R, Hurley B, Jacewicz M, Acheson DW, Keusch GT. Shiga toxins do not directly stimulate alpha-granule secretion or enhance aggregation of human platelets. Acta Haematol. 1999; 102(1):51-5. PMID: 10473889.

    Citations: 4   Fields:

    Translation:HumansCellsCT

  • Flaumenhaft R, Abe M, Sato Y, Miyazono K, Harpel J, Heldin CH, Rifkin DB. Role of the latent TGF-beta binding protein in the activation of latent TGF-beta by co-cultures of endothelial and smooth muscle cells. J Cell Biol. 1993 Feb; 120(4):995-1002.PMID: 8432736.

    Citations: 46  

    35 readers on Mendeley

     

    Translation:AnimalsCells

  • Flaumenhaft R, Kojima S, Abe M, Rifkin DB. Activation of latent transforming growth factor beta. Adv Pharmacol. 1993; 24:51-76. PMID: 8504067.

    Citations: 20   Fields:

    Translation:HumansAnimals

  • Flaumenhaft R, Rifkin DB. The extracellular regulation of growth factor action. Mol Biol Cell. 1992 Oct; 3(10):1057-65. PMID: 1421565.

    Citations: 32   Fields:

    Translation:HumansAnimalsCells

  • Flaumenhaft R, Abe M, Mignatti P, Rifkin DB. Basic fibroblast growth factor-induced activation of latent transforming growth factor beta in endothelial cells: regulation of plasminogen activator activity. J Cell Biol. 1992 Aug; 118(4):901-9. PMID: 1380001.

    Citations: 35  

    23 readers on Mendeley

    Translation:AnimalsCells

  • Flaumenhaft R, Rifkin DB. Cell density dependent effects of TGF-beta demonstrated by a plasminogen activator-based assay for TGF-beta. J Cell Physiol. 1992 Jul; 152(1):48-55. PMID: 1618922.

    Citations: 4   Fields:

    Translation:AnimalsCells

  • Flaumenhaft R, Rifkin DB. Extracellular matrix regulation of growth factor and protease activity. Curr Opin Cell Biol. 1991 Oct; 3(5):817-23. PMID: 1931082.

    Citations: 21   Fields:

    Translation:HumansAnimalsCells

  • Moscatelli D, Flaumenhaft R, Saksela O. Interaction of basic fibroblast growth factor with extracellular matrix and receptors. Ann N Y Acad Sci. 1991; 638:177-81. PMID: 1664684.

    Citations: 1   Fields:

    Translation:AnimalsCells

  • Rifkin DB, Moscatelli D, Flaumenhaft R, Sato Y, Saksela O, Tsuboi R. Mechanisms controlling the extracellular activity of basic fibroblast growth factor and transforming growth factor. Ann N Y Acad Sci. 1991; 614:250-8. PMID: 2024887.

    Citations: 1   Fields:

    Translation:HumansAnimalsCells

  • Rifkin DB, Moscatelli D, Bizik J, Quarto N, Blei F, Dennis P, Flaumenhaft R, Mignatti P. Growth factor control of extracellular proteolysis. Cell Differ Dev. 1990 Dec 02; 32(3):313-8. PMID: 1711916.

    Citations: 15   Fields:

    Translation:AnimalsCells

  • Flaumenhaft R, Moscatelli D, Rifkin DB. Heparin and heparan sulfate increase the radius of diffusion and action of basic fibroblast growth factor. J Cell Biol. 1990 Oct; 111(4):1651-9. PMID: 2170425.

    Citations: 40  

    23 readers on Mendeley

     

    Translation:AnimalsCells

  • Flaumenhaft R, Moscatelli D, Saksela O, Rifkin DB. Role of extracellular matrix in the action of basic fibroblast growth factor: matrix as a source of growth factor for long-term stimulation of plasminogen activator production and DNA synthesis. J Cell Physiol. 1989 Jul; 140(1):75-81. PMID: 2738111.

    Citations: 32   Fields:

    Translation:AnimalsCells

SOURCE

https://connects.catalyst.harvard.edu/profiles/display/Person/27465

https://www.bidmc.org/research/research-by-department/medicine/hemostasis-and-thrombosis/flaumenhaft-lab/research-interests

 

 

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Lesson 8 Cell Signaling and Motility: Lesson and Supplemental Information on Cell Junctions and ECM: #TUBiol3373

Posted in Biological Networks, Bone Disease and Musculoskeletal Disease, Cancer - General, Cardiovascular Research, Cell Biology, Cell Biology, Signaling & Cell Circuits, Coagulation Therapy and Internal Bleeding, Cytoskeleton, Developmental biology, Disease Biology, Electrophysiology, Endoplasmic reticulum, tagged , , , , , , , , , , , , , , on April 9, 2019| Leave a Comment »

Lesson 8 Cell Signaling and Motility: Lesson and Supplemental Information on Cell Junctions and ECM: #TUBiol3373

Curator: Stephen J. Williams, Ph.D.

Please click on the following link for the PowerPoint Presentation for Lecture 8 on Cell Junctions and the  Extracellular Matrix: (this is same lesson from 2018 so don’t worry that file says 2018)

cell signaling 8 lesson 2018

 

Some other reading on this lesson on this Open Access Journal Include:

On Cell Junctions:

Translational Research on the Mechanism of Water and Electrolyte Movements into the Cell     

(pay particular attention to article by Fischbarg on importance of tight junctions for proper water and electrolyte movement)

The Role of Tight Junction Proteins in Water and Electrolyte Transport

(pay attention to article of role of tight junction in kidney in the Loop of Henle and the collecting tubule)

EpCAM [7.4]

(a tight junction protein)

Signaling and Signaling Pathways

(for this lesson pay attention to the part that shows how Receptor Tyrosine Kinase activation (RTK) can lead to signaling to an integrin and also how the thrombin receptor leads to cellular signals both to GPCR (G-protein coupled receptors like the thrombin receptor, the ADP receptor; but also the signaling cascades that lead to integrin activation of integrins leading to adhesion to insoluble fibrin mesh of the newly formed clot and subsequent adhesion of platelets, forming the platelet plug during thrombosis.)

On the Extracellular Matrix

Three-Dimensional Fibroblast Matrix Improves Left Ventricular Function Post MI

Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel

 

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The Promise of Low-Dose Aspirin on Longevity in the Geriatric Population: No Effect on Outcomes in the US and Australia

Posted in Atherogenic Processes & Pathology, Cardiovascular Research, Coagulation Therapy and Internal Bleeding, Frontiers in Cardiology and Cardiovascular Disorders, HTN, inflammation independent of lipid levels, Pharmacotherapy of Cardiovascular Disease, Stroke on September 24, 2018| Leave a Comment »

The Promise of Low-Dose Aspirin on Longevity in the Geriatric Population: No Effect on Outcomes in the US and Australia

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 10/17/2018

https://www.nejm.org/doi/full/10.1056/NEJMoa1800722

Effect of Aspirin on Disability-free Survival in the Elderly

ORIGINAL ARTICLE

Effect of Aspirin on Disability-free Survival in the Healthy Elderly

J.J. McNeil and Others

    

McNeil et al. conducted the randomized, placebo-controlled Aspirin in Reducing Events in the Elderly (ASPREE) trial to investigate whether the daily use of aspirin, at a dose of 100 mg, in healthy, community-dwelling older adults would prolong a healthy life span, free from dementia and persistent physical disability. Trial participants were community-dwelling men and women from Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States).

Clinical Pearls

  Is there any evidence to support the use of aspirin for primary prevention of cardiovascular or other chronic disease in healthy older adults?

Several large, randomized trials have shown the efficacy of aspirin for the secondary prevention of cardiovascular disease among persons with a history of coronary heart disease or stroke. The evidence supporting a benefit of aspirin therapy in the primary prevention of cardiovascular or other chronic disease is less conclusive despite favorable trends suggesting that aspirin use reduces the incidence of cardiovascular events and possibly reduces the incidence of cancer and cancer-related mortality, particularly from colorectal cancer.

  Does the daily use of 100 mg of aspirin prolong a healthy lifespan in older adults without cardiovascular disease, dementia, or physical disability?

In the ASPREE trial, the daily use of 100 mg of enteric-coated aspirin did not differ significantly from placebo in influencing the rates of disability-free survival at a median of 4.7 years. The primary end point of death, dementia, or physical disability occurred in 921 participants in the aspirin group (21.5 events per 1000 person-years) and in 914 in the placebo group (21.2 events per 1000 person-years). The between-group difference was not significant (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11; P=0.79). Among participants who had a primary end-point event, death was the most common first event (in 911 participants [50% of the events] at a mean age of 77.5 years), dementia was the next most common (in 549 participants [30% of the events] at a mean age of 77.7 years), and persistent physical disability was the least common.

Morning Report Questions

Q. How does a daily aspirin dose of 100 mg influence rates of death from any cause and the risk of major hemorrhage in healthy older adults?

A. In the ASPREE trial, the secondary end point of death from any cause, denoting death as the first, second, or third event to occur in the primary end point, occurred in 558 participants in the aspirin group (12.7 events per 1000 person-years) and in 494 participants in the placebo group (11.1 events per 1000 person-years) (hazard ratio, 1.14; unadjusted 95% CI, 1.01 to 1.29). Because there was no adjustment for multiple comparisons of secondary end points, no inferences can be made regarding differences in mortality between the two groups. Major hemorrhage occurred in 3.8% of the participants in the aspirin group, as compared with 2.8% of those in the placebo group (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001). Fatal or nonfatal hemorrhagic stroke (including subarachnoid hemorrhage) occurred in 49 participants (0.5%) in the aspirin group and in 40 (0.4%) in the placebo group.

Q. How generalizable are the results of the ASPREE trial?

A. White participants comprised 91% of the overall trial cohort. Owing to the small number of blacks and Hispanics (including participants who were younger than 70 years of age) and other nonwhites, the applicability of the main findings of the ASPREE trial to these subgroups is unclear.

 

Daily Low-Dose Aspirin Found to Have No Effect on Healthy Life Span in Older People?

According to 3 articles published online The New England Journal of Medicine (16 September 2018), daily low-dose aspirin was found to have no effect on healthy life span in older people. This large NIH-funded study examined outcomes in United States and Australia

Results showed that in a large clinical trial to determine the risks and benefits of daily low-dose aspirin in healthy older adults without previous cardiovascular events,

Aspirin did not prolong healthy, independent living (life free of dementia or persistent physical disability).

Risk of dying from a range of causes, including cancer and heart disease, varied and will require further analysis and additional follow-up of study participants. These initial findings from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, partially supported by the National Institutes of Health.

ASPREE is an international, randomized, double-blind, placebo-controlled trial that enrolled 19,114 older people (16,703 in Australia and 2,411 in the United States). The study began in 2010 and enrolled participants aged 70 and older; 65 was the minimum age of entry for African-American and Hispanic individuals in the United States because of their higher risk for dementia and cardiovascular disease. At study enrollment, ASPREE participants could not have dementia or a physical disability and had to be free of medical conditions requiring aspirin use. They were followed for an average of 4.7 years to determine outcomes.

In the total study population, treatment with 100 mg of low-dose aspirin per day did not affect survival free of dementia or disability. Among the people randomly assigned to take aspirin,

  • 90.3% remained alive at the end of the treatment without persistent physical disability or dementia, compared with 90.5% of those taking a placebo.
  • Rates of physical disability were similar, and rates of dementia were almost identical in both groups. However,
  • the group taking aspirin had an increased risk of death compared to the placebo group: 5.9% of participants taking aspirin and 5.2% taking placebo died during the study.

This effect of aspirin has not been noted in previous studies; and caution is needed in interpreting this finding. The higher death rate in the aspirin-treated group was due primarily to a higher rate of cancer deaths. A small increase in new cancer cases was reported in the group taking aspirin but the difference could have been due to chance. The authors also analyzed the ASPREE results to determine whether cardiovascular events took place. They found that

  • the rates for major cardiovascular events — including coronary heart disease, nonfatal heart attacks, and fatal and nonfatal ischemic stroke — were similar in the aspirin and the placebo groups. In the aspirin group, 448 people experienced cardiovascular events, compared with 474 people in the placebo group.

Significant bleeding — a known risk of regular aspirin use — was also measured. The authors noted that

  • aspirin was associated with a significantly increased risk of bleeding, primarily in the gastrointestinal tract and brain. Clinically significant bleeding — hemorrhagic stroke, bleeding in the brain, gastrointestinal hemorrhages or hemorrhages at other sites that required transfusion or hospitalization — occurred in 361 people (3.8%) on aspirin and in 265 (2.7%) taking the placebo.
  • As would be expected in an older adult population, cancer was a common cause of death, and 50% of the people who died in the trial had some type of cancer.
  • Heart disease and stroke accounted for 19% of the deaths and major bleeding for 5%.

The ASPREE team is continuing to analyze the results of this study and has implemented plans for monitoring participants. As these efforts continue, the authors emphasized that older adults should follow the advice from their own physicians about daily aspirin use. It is important to note that the new findings do not apply to people with a proven indication for aspirin such as stroke, heart attack or other cardiovascular disease. In addition, the study did not address aspirin’s effects in people younger than age 65. Also, since only 11% of participants had regularly taken low-dose aspirin prior to entering the study, the implications of ASPREE’s findings need further investigation to determine whether healthy older people who have been regularly using aspirin for disease prevention should continue or discontinue use.

SOURCE

From: OnTarget <ontarget@targethealth.com>

Date: September 23, 2018 at 10:47:06 PM EDT

To: avivalev-ari@alum.berkeley.edu

Subject: OnTarget Newsletter

 

Other 121 articles on ASPIRIN were published in this Open Access Online Scientific Journal, including the following:

https://pharmaceuticalintelligence.com/?s=Aspirin

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Two Classes of Antithrombotic Drugs: Anticoagulants and Antiplatelet drugs

Posted in Acute coronary syndrome, Acute Myocardial Infarction, Atherogenic Processes & Pathology, Cardiovascular Research, Coagulation Therapy and Internal Bleeding, congestive heart failure, endovascular thrombectomy, Frontiers in Cardiology and Cardiovascular Disorders, Hematology, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Stents & Tools, Stroke, Valves & Tools, Vascular Diseases on June 25, 2018| Leave a Comment »

UPDATED on 2/25/2019

https://www.medpagetoday.com/cardiology/prevention/78202?xid=nl_mpt_SRCardiology_2019-02 25&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=CardioUpdate_022519&utm_term=NL_Spec_Cardiology_Update_Active

 

ICER announced plans to look at icosapent ethyl (Vascepa) and rivaroxaban (Xarelto) as add-on therapies in cardiovascular disease.

Heart attack risk is rising among young women. But NHANES data show women are still ahead of men on control of hypertension, diabetes, and cholesterol. (Circulation)

Two Classes of Antithrombotic Drugs: Anticoagulants and Antiplatelet drugs

Reporter: Aviva Lev-Ari, PhD, RN
These drugs are used to treat
  • strokes,
  • myocardial infarctions,
  • pulmonary embolisms,
  • disseminated intravascular coagulation (DIC) and
  • deep vein thrombosis (DVT)
— all potentially life-threatening conditions.
THERAPEUTIC STRATEGIES
• Degrade fibrinogen/fibrin (fibrinolytic agents)
GOAL: eliminate formed clots
• Inhibit clotting mechanism (anticoagulants)
GOAL: prevent progression of thrombosis
• Interfere either with platelet adhesion and/or aggregation (antiplatelet drugs)
GOAL: prevent initial clot formation
Antithrombotic therapy has had an enormous impact in several significant ways.
  • Heparin has made bypass surgery and dialysis possible by blocking clotting in external tubing.
  • Antithrombotic therapy has reduced the risk of blood clots in leg veins (also known as deep-vein thrombosis or DVT), a condition that can lead to death from pulmonary embolism (a clot that blocks an artery to the lungs) by more than 70 percent. And most importantly,
  • it has markedly reduced death from heart attacks, the risk of stroke in people with heart irregularities (atrial fibrillation), and the risk of major stroke in patients with mini-strokes.

Antithrombotic Therapy

This article was published in December 2008 as part of the special ASH anniversary brochure, 50 Years in Hematology: Research That Revolutionized Patient Care.

Normally, blood flows through our arteries and veins smoothly and efficiently, but if a clot, or thrombus, blocks the smooth flow of blood, the result – called thrombosis – can be serious and even cause death. Diseases arising from clots in blood vessels include heart attack and stroke, among others. These disorders collectively are the most common cause of death and disability in the developed world. We now have an array of drugs that can be used to prevent and treat thrombosis – and there are more on the way – but this was not always the case.

Classes of Antithrombotic Drugs

Image Source: http://www.hematology.org/About/History/50-Years/1523.aspx

The most important components of a thrombus are fibrin and platelets. Fibrin is a protein that forms a mesh that traps red blood cells, while platelets, a type of blood cell, form clumps that add to the mass of the thrombus. Both fibrin and platelets stabilize the thrombus and prevent it from falling apart. Fibrin is the more important component of clots that form in veins, and platelets are the more important component of clots that form in arteries where they can cause heart attacks and strokes by blocking the flow of blood in the heart and brain, respectively, although fibrin plays an important role in arterial thrombosis as well.

There are two classes of antithrombotic drugs: anticoagulants and antiplatelet drugs. Anticoagulants slow down clotting, thereby reducing fibrin formation and preventing clots from forming and growing. Antiplatelet agents prevent platelets from clumping and also prevent clots from forming and growing.

Anticoagulant Drugs

The anticoagulants heparin and dicumarol were discovered by chance, long before we understood how they worked. Heparin was first discovered in 1916 by a medical student at The Johns Hopkins University who was investigating a clotting product from extracts of dog liver and heart. In 1939, dicumarol (the precursor to warfarin) was extracted by a biochemist at the University of Wisconsin from moldy clover brought to him by a farmer whose prize bull had bled to death after eating the clover.

Both of these anticoagulants have been used effectively to prevent clots since 1940. These drugs produce a highly variable anticoagulant effect in patients, requiring their effect to be measured by special blood tests and their dose adjusted according to the results. Heparin acts immediately and is given intravenously (through the veins). Warfarin is swallowed in tablet form, but its anticoagulant effect is delayed for days. Therefore, until recently, patients requiring anticoagulants who were admitted to a hospital were started on a heparin infusion and were then discharged from the hospital after five to seven days on warfarin.

In the 1970s, three different groups of researchers in Stockholm, London, and Hamilton, Ontario, began work on low-molecular-weight heparin (LMWH). LMWH is produced by chemically splitting heparin into one-third of its original size. It has fewer side effects than heparin and produces a more predictable anticoagulant response. By the mid 1980s, LMWH preparations were being tested in clinical trials, and they have now replaced heparin for most indications. Because LMWH is injected subcutaneously (under the skin) in a fixed dose without the need for anticoagulant monitoring, patients can now be treated at home instead of at the hospital.

With the biotechnology revolution has come genetically engineered “designer” anticoagulant molecules that target specific clotting enzymes. Anti-clotting substances and their DNA were also extracted from an array of exotic creatures (ticks, leeches, snakes, and vampire bats) and converted into drugs by chemical synthesis or genetic engineering. Structural chemists next began to fabricate small molecules designed to fit into the active component of clotting enzymes, like a key into a lock.

The first successful synthetic anticoagulants were fondaparinux and bivalirudin. Bivalirudin, a synthetic molecule based on the structure of hirudin (the anti-clotting substance found in leeches), is an effective treatment for patients with heart attacks. Fondaparinux is a small molecule whose structure is based on the active component of the much larger LMWH and heparin molecules. It has advantages over LMWH and heparin and has recently been approved by the FDA. Newer designer drugs that target single clotting factors and that can be taken by mouth are undergoing clinical testing. If successful, we will have safer and more convenient replacements for warfarin, the only oral anticoagulant available for more than 60 years.

Antiplatelet Drugs

Blood platelets are inactive until damage to blood vessels or blood coagulation causes them to explode into sticky irregular cells that clump together and form a thrombus. The first antiplatelet drug was aspirin, which has been used to relieve pain for more than 100 years. In the mid-1960s, scientists showed that aspirin prevented platelets from clumping, and subsequent clinical trials showed that it reduces the risk of stroke and heart attack. In 1980, researchers showed that aspirin in very low doses (much lower than that required to relieve a headache) blocked the production of a chemical in platelets that is required for platelet clumping. During that time, better understanding of the process of platelet clumping allowed the development of designer antiplatelet drugs directed at specific targets. We now have more potent drugs, such as clopidogrel, dipyridamole, and abciximab. These drugs are used with aspirin and effectively prevent heart attack and stroke; they also prolong the lives of patients who have already had a heart attack.

SOURCE 
Anticoagulation Drugs:
  • heparin (FONDAPARINUX HEPARIN (Calciparine, Hepathrom, Lipo-Hepin, Liquaemin, Panheprin)
  • warfarin – 4-HYDROXYCOUMARIN (Coumadin) WARFARIN (Athrombin-K, Panwarfin)
  • rivaroxaban (Xarelto)
  • dabigatran (Pradaxa)
  • apixaban (Eliquis)
  • edoxaban (Savaysa)
  • enoxaparin (Lovenox)
  • fondaparinux (Arixtra)
  • ARGATROBAN BIVALIRUDIN (Angiomax)
  • DALTEPARIN (Fragmin)
  • DROTRECOGIN ALFA (ACTIVATED PROTEIN C) (Xigris)
  • HIRUDIN (Desirudin)
  • LEPIRUDIN (Refludan)
  • XIMELAGATRAN (Exanta)

ANTIDOTES

  • PHYTONADIONE (Vitamin K1)
  • PROTAMINE SULFATE AMINOCAPROIC ACID (EACA) (generic, Amicar) (in bleeding disorders)
Antiplatelet Drugs
  • ACETYL SALICYLIC ACID (aspirin) 
  • clopidogrel (Plavix)
  • dipyridamole (Persantine)
  • abciximab (Centocor)
  • EPTIFIBATIDE (Integrilin)
  • TICLOPIDINE (Ticlid)
  • TIROFIBAN (Aggrastat)

THROMBOLYTICS

  1. ANISTREPLASE (APSAC; Eminase)
  2. STREPTOKINASE (Streptase, Kabikinase)
  3. TISSUE PLASMINOGEN ACTIVATORS (tPAs):
  • ALTEPLASE (Activase),
  • RETEPLASE (Retavase),
  • TENECTEPLASE (TNKase)
  • UROKINASE (Abbokinase)

Fibrinolytic Drugs

Fibrinolytic therapy is used in selected patients with venous thromboembolism. For example, patients with massive or submassive PE can benefit from systemic or catheter-directed fibrinolytic therapy. The latter can also be used as an adjunct to anticoagulants for treatment of patients with extensive iliofemoral-vein thrombosis.

Arterial and venous thrombi are composed of platelets and fibrin, but the proportions differ.

  • Arterial thrombi are rich in platelets because of the high shear in the injured arteries. In contrast,
  • venous thrombi, which form under low shear conditions, contain relatively few platelets and are predominantly composed of fibrin and trapped red cells.
  • Because of the predominance of platelets, arterial thrombi appear white, whereas venous thrombi are red in color, reflecting the trapped red cells.

SOURCE

https://accessmedicine.mhmedical.com/content.aspx?bookid=331&sectionid=40726858

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Advantages and Disadvantages of Novel Oral Anticoagulants (NOACs)

Posted in Coagulation Therapy and Internal Bleeding, tagged , , , , on March 20, 2018| Leave a Comment »

Advantages and Disadvantages of Novel Oral Anticoagulants (NOACs)

 

Reporter: Aviva Lev-Ari, PhD, RN

 

 

UPDATED ON 2/1/2019

NOACs Usually Preferable to Warfarin in Atrial Fibrillation: Guideline Update

READ ALL GUIDELINES at the sources listed below.

Here we post only,

Triple vs Double Antithrombotic Therapy

The update provides a warning about the extra bleeding risk associated with OAC in patients with AF who have undergone percutaneous coronary intervention (PCI) for ACS, who otherwise would also receive dual antiplatelet therapy (DAPT). Such “triple therapy” is usually best avoided, it emphasizes.

In patients with increased stroke risk (based on a CHA2DS2-VASc ≥2) who’ve had PCI for ACS, the update states, “double therapy” with P2Y12 inhibitor antiplatelets plus a dose-adjusted vitamin-K antagonist, low-dose rivaroxaban, or 150 mg bid dabigatran “is reasonable to reduce the risk of bleeding compared with triple therapy.” The recommendations are IIa, level of evidence B-R.

“The guideline acknowledges that if there’s a need to put them on triple therapy, it should only be for a short period of time: 4 to 6 weeks, for example,” January said. Following that early post-PCI period in which stent thrombosis is most likely, the patient should preferably be transitioned to double therapy.

“DAPT alone may be considered for patients with ACS who have AF and a CHA2DS2-VASc score of 0 to 1, with reconsideration of the indications for anticoagulation over time,” the new document says.

January reported no conflicts. Disclosure information for all writing committee members and reviewers is in the report and tabulated separately online.

Original Publications:
  • Circulation. Published online January 28, 2019. Report
  • J Am Coll Cardiol. Published online January 28, 2019. Report
  • Heart Rhythm. Published online January 28, 2019. Report

SOURCE

https://www.medscape.com/viewarticle/908490?nlid=127677_3802&src=WNL_mdplsnews_190201_mscpedit_card&uac=93761AJ&spon=2&impID=1874163&faf=1

 

 

In the past four years, three novel oral anticoagulant (NOAC) medications have become available:

  • apixaban (Eliquis®),
  • dabigatran (Pradaxa®), and
  • rivaroxaban (Xarelto®). A fourth NOAC,
  • edoxaban (Savaysa™), has been submitted for approval by the US Food and Drug Administration …

Two small to moderate size trials have shown similar bleeding risk with other NOACs (VENTURE-AF with rivaroxaban [Xarelto] and RE-CIRCUIT with dabigatran [Pradaxa]) compared with vitamin K antagonists. In a non-formal “eyeball” meta-analysis with AXAFA-AFNET 5, combined death, stroke or transient ischemic attack, and major bleeding risk appeared to trend lower with a NOAC than vitamin K antagonist.

However, “differences in populations and procedures may well explain the different outcomes in bleeding rates and silent strokes with NOAC versus vitamin K antagonists,” suggested Blomstrom-Lundqvist.

SOURCE

Increased Bleeding is Main Issue With Newer Agents

Regardless of which agent is used, clinical practice and research has shifted focus to decreasing the risk of bleeding for patients on oral anticoagulants and antithrombotics. While the newer agents might be better than warfarin on several points, the more effective ability to prevent clotting also results in the unwanted consequence of increased bleeding. This sentiment was echoed multiple times by speakers at ACC.16. The most common bleeding complication with NOACs compared to warfarin is gastrointestinal (GI) bleeding.  The results of the Ruff meta-analysis favored warfarin over NOACs for rates of GI bleeds (whether results from dabigatran trials were included or not).

“Major bleeds, as well as minor bleeds, may be a problem because patients stop their treatments — not only their antithrombotic treatment, but also the ACE inhibitors, statins and all other life-saving therapies,” explained Freek Verheugt, M.D., FESC, FACC, FAHA, professor of cardiology, Heart-Lung Centre of the University Medical Centre of Nijmegen and chairman of the Department of Cardiology at Onze Lieve Vrouwe Gasthuis, The Netherlands.

Evolution of the Anticoagulant Nomenclature 

The approval of dabigatran (Pradaxa) in 2010 lead to the creation of the term new oral anticoagulants (NOACs). This term was changed to novel oral anticoagulants (NOACs) when rivaroxaban (Xarelto) came to the market in 2011. After apixaban (Eliquis) and edoxaban (Savaysa) were cleared, the name changed to direct oral anticoagulants (DOACs) and is the term used by the International Society of Thrombosis and Haemostasis. Alternative names for these agents are target-specific oral anticoagulants (TSOACs) and non-vitamin K oral anticoagulants (NOACs), the term used by the American College of Chest Physicians and the FDA. All of these acronyms refer to the same agents.

SOURCE

 

Warfarin Use May Not Bring Long-Term Stability for Atrial Fibrillation

Registry study finds INR values fluctuate over 18 months, even in patients considered “stable”

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FDA Approval marks first presentation of bivalirudin in frozen, premixed, ready-to-use formulation

Posted in Cardiac and Cardiovascular Surgical Procedures, Coagulation Therapy and Internal Bleeding, PCI, Peripheral Arterial Disease & Peripheral Vascular Surgery on January 24, 2018| Leave a Comment »

FDA Approval marks first presentation of bivalirudin in frozen, premixed, ready-to-use formulation

Reporter: Aviva Lev-Ari, PhD, RN

 

Baxter Announces FDA Approval of Ready-to-Use Cardiovascular Medication Bivalirudin

Approval marks first presentation of bivalirudin in frozen, premixed, ready-to-use formulation

https://www.dicardiology.com/product/baxter-announces-fda-approval-ready-use-cardiovascular-medication-bivalirudin?eid=333021707&bid=1983307

Dosing and Uses

https://reference.medscape.com/drug/angiomax-angiox-bivalirudin-342137

 

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Shaun Coughlin from UCSF Cardiovascular Research Center to cardio group for the Novartis Institute for Biomedical Research in Cambridge, MA

Posted in Coagulation Therapy and Internal Bleeding, Scientist: Career considerations, tagged on August 17, 2017| Leave a Comment »

Shaun Coughlin from UCSF Cardiovascular Research Center to cardio group for the Novartis Institute for Biomedical Research in Cambridge, MA

Reporter: Aviva Lev-Ari, PhD, RN

 

The dean of the UCSF med school, Talmadge King, had this to say in his sendoff today:

Coughlin’s “research discoveries revealed a mechanism by which proteases regulate cellular behaviors including a key mechanism that controls blood platelet activation and clot formation. This work led to a new medical therapy for preventing heart attacks and strokes and has been honored by the American Heart Association’s Basic Science Award in 2003 and its Research Achievement Award in 2014. Among his numerous other awards are the Bristol-Myers Squibb Cardiovascular Research Award and the Distinguished Career Award from the International Society on Thrombosis and Haemostasis.”

SOURCE

https://endpts.com/top-ucsf-scientist-shaun-coughlin-joins-migration-to-big-pharma-leaping-to-novartis

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Vena Cava Filters: Device for Prevention of Pulmonary Embolism and Thrombosis

Posted in Atherogenic Processes & Pathology, Atrial Fibrilation (a-Fib), Cardiac Pacing and Arrhythmias, Cardiac and Cardiovascular Surgical Procedures, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Coagulation Therapy and Internal Bleeding, congestive heart failure, Frontiers in Cardiology and Cardiovascular Disorders, Heart Failure (HF), Medical Devices R&D and Inventions, Origins of Cardiovascular Disease, Peripheral Arterial Disease & Peripheral Vascular Surgery, Pharmacotherapy of Cardiovascular Disease, Vascular Diseases, Vena Caval Filters: Device for Prevention of Pulmonary Embolism and Thrombosis, tagged , , , , , on October 4, 2016| Leave a Comment »

Inferior Vena Cava Filters: Device for Prevention of Pulmonary Embolism and Thrombosis

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 7/18/2018

 

Original Investigation
Cardiology
July 13, 2018

Association of Inferior Vena Cava Filter Placement for Venous Thromboembolic Disease and a Contraindication to Anticoagulation With 30-Day Mortality

Tyson E. Turner, MD, MPH1; Mohammed J. Saeed, MBChB, MPH2; Eric Novak, MS1; et alDavid L. Brown, MD1
Author Affiliations Article Information
JAMA Network Open. 2018;1(3):e180452. doi:10.1001/jamanetworkopen.2018.0452
Key Points

Question  What is the association of inferior vena cava filter placement with 30-day mortality in patients with venous thromboembolic disease and a contraindication to anticoagulation?

Findings  In this cohort study, using 2 different statistical methods with adjustment for immortal time bias, inferior vena cava filter placement in patients with venous thromboembolic disease and a contraindication to anticoagulation was associated with an increased risk of 30-day mortality.

Meaning  Randomized clinical trials are needed to define the role of inferior vena cava filter placement in patients with venous thromboembolic disease and a contraindication to anticoagulation.

 

Abstract

Importance  Despite the absence of data from randomized clinical trials, professional societies recommend inferior vena cava (IVC) filters for patients with venous thromboembolic disease (VTE) and a contraindication to anticoagulation therapy. Prior observational studies of IVC filters have suggested a mortality benefit associated with IVC filter insertion but have often failed to adjust for immortal time bias, which is the time before IVC filter insertion, during which death can only occur in the control group.

Objective  To determine the association of IVC filter placement with 30-day mortality after adjustment for immortal time bias.

Design, Setting, and Participants  This comparative effectiveness, retrospective cohort study used a population-based sample of hospitalized patients with VTE and a contraindication to anticoagulation using the State Inpatient Database and the State Emergency Department Database, part of the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, from hospitals in California (January 1, 2005, to December 31, 2011), Florida (January 1, 2005, to December 31, 2013), and New York (January 1, 2005, to December 31, 2012). Data analysis was conducted from September 15, 2015, to March 14, 2018.

Exposure  Inferior vena cava filter placement.

Main Outcomes and Measures  Multivariable Cox proportional hazard models were constructed with IVC filters as a time-dependent variable that adjusts for immortal time bias. The Cox model was further adjusted using the propensity score as an adjustment variable.

Results  Of 126 030 patients with VTE, 61 281 (48.6%) were male and the mean (SD) age was 66.9 (16.6) years. In this cohort, 45 771 (36.3%) were treated with an IVC filter, whereas 80 259 (63.7%) did not receive a filter. In the Cox model with IVC filter status analyzed as a time-dependent variable to account for immortal time bias, IVC filter placement was associated with a significantly increased hazard ratio of 30-day mortality (1.18; 95% CI, 1.13-1.22; P < .001). When the propensity score was included in the Cox model, IVC filter placement remained associated with an increased hazard ratio of 30-day mortality (1.18; 95% CI, 1.13-1.22; P < .001).

Conclusions and Relevance  After adjustment for immortal time bias, IVC filter placement was associated with increased 30-day mortality in patients with VTE and a contraindication to anticoagulation. Randomized clinical trials are needed to determine the efficacy of IVC filter placement in patients with VTE and a contraindication to anticoagulation.

 

EDITORIAL

Requiem for Liberalizing Indications for Vena Caval Filters?

Samuel Z. Goldhaber
http://dx.doi.org/10.1161/CIRCULATIONAHA.116.022730 Published: May 24, 2016

Use of inferior vena caval (IVC) filters has proliferated.

  • In 1979, ≈2000 vena caval filters were inserted.
  • In 1999, the number of IVC filters inserted annually had increased ≈25-fold to 49 000.
  • Retrievable IVC filters were first approved in 2003 and gained popularity rapidly.
  • By 2006, retrievable IVC filters accounted for about half of all IVC filters that were inserted.
  • The largest proportional increase in IVC filter use was subsequently in patients at risk for pulmonary embolism (PE) but who had had neither PE nor deep vein thrombosis (DVT).1

The Controversy by Samuel Z. Goldhaber, MD

Appropriate use of IVC filters is a hot topic. On the one hand,

  • filters hold the promise of reducing PE rates by trapping moderate and large DVT that have detached from the deep veins of the legs and pelvis and that are hurtling toward the heart. On the other hand, we do not have clear-cut definitions of which patients with PE and DVT will benefit most from this technology.
  • an array of complications can ensue, including
  1. caval perforation,2
  2. caval thrombosis,
  3. fracture,
  4. fragment embolization,
  5. intracardiac migration,3
  6. cardiac perforation, and
  7. cardiac tamponade.4

In a systematic review of retrievable IVC filters, only 34% were retrieved, and the majority remained in place permanently. Most of the complications from retrievable filters occurred with long-term use.5

Guidelines

However, it is premature to hammer nails into the coffin and to gather as a medical community for a requiem that celebrates no indication for liberalizing indications for placing an IVC filter. Instead, we need to shift the focus of the questions that we investigate and pour resources into further randomized and observational trials of IVC filter insertion in special highrisk populations.

There remain important groups of patients who may benefit from IVC filters with reduction in PE and PE-associated mortality (Table 2). In some cases, tantalizing data suggest that these populations warrant filters. In other cases, we lack data to guide us. Patients with massive PE—accompanied by cardiogenic shock requiring vasopressors to support blood pressure—are desperately ill. They are clinically unstable. An additional PE under these circumstances can be the fatal blow. Data from the National Inpatient Sample and the International Cooperative PE Registry suggest that filters in these patients may be lifesaving.

Patients with severe PE who undergo acute surgical pulmonary embolectomy are vulnerable to recurrent PE, especially during the early postoperative period where full anticoagulation cannot be immediately implemented. I have had personal experience managing this type of patient where the embolectomy is successful but the patient dies of recurrent PE.19

Table 1. Generally Accepted Consensus Recommendations for IVC Filter Insertion in Patients With VTE

  • Major bleeding on full-dose anticoagulation
  • Major contraindication to full-dose anticoagulation
  • New-onset acute PE (especially recurrent PE) despite well-documented fulldose anticoagulation for an existing VTE

IVC indicates inferior vena caval; PE, pulmonary embolism; and VTE, venous thromboembolism.

 

Table 2. Special Populations Where Benefits of IVC Filter Insertion May Outweigh Risks

  • Massive PE or high-risk submassive PE
  • Surgical pulmonary embolectomy
  • Cancer patients with VTE or at high risk of VTE with concomitant high risk of bleeding if anticoagulated
  • Surgical patients (especially during preoperative evaluation) at high risk of VTE with concomitant high risk of bleeding if anticoagulated

IVC indicates inferior vena caval; PE, pulmonary embolism; and VTE, venous thromboembolism.

http://dx.doi.org/10.1161/CIRCULATIONAHA.116.022730

References

1. Stein PD, Matta F, Hull RD. Increasing use of vena cava filters for prevention of pulmonary embolism. Am J Med. 2011;124:655–661. doi:10.1016/j.amjmed.2011.02.021.

2. Jia Z, Wu A, Tam M, Spain J, McKinney JM, Wang W. Caval penetration by inferior vena cava filters: a systematic literature review of clinical significance and management. Circulation. 2015;132:944–952. doi: 10.1161/ CIRCULATIONAHA.115.016468

3. Owens CA, Bui JT, Knuttinen MG, Gaba RC, Carrillo TC, Hoefling N, Layden-Almer JE. Intracardiac migration of inferior vena cava filters: review of published data. Chest. 2009;136:877–887. doi: 10.1378/ chest.09-0153.

4. Nicholson W, Nicholson WJ, Tolerico P, Taylor B, Solomon S, Schryver T, McCullum K, Goldberg H, Mills J, Schuler B, Shears L, Siddoway L, Agarwal N, Tuohy C. Prevalence of fracture and fragment embolization of Bard retrievable vena cava filters and clinical implications including cardiac perforation and tamponade. Arch Intern Med. 2010;170:1827–1831. doi: 10.1001/archinternmed.2010.316.

5. Angel LF, Tapson V, Galgon RE, Restrepo MI, Kaufman J. Systematic review of the use of retrievable inferior vena cava filters. J Vasc Interv Radiol. 2011;22:1522–1530.e3. doi: 10.1016/j.jvir.2011.08.024.

19. Aklog L, Williams CS, Byrne JG, Goldhaber SZ. Acute pulmonary embolectomy: a contemporary approach. Circulation. 2002;105:1416–1419.

Other related articles published in this Open Access Online Scientific Journal include the follwoing:

 

Xarelto (Rivaroxaban): Anticoagulant Therapy gains FDA New Indications and Risk Reduction for: (DVT) and (PE), while in use for Atrial fibrillation increase in Gastrointestinal (GI) Bleeding Reported

https://pharmaceuticalintelligence.com/2012/11/04/xarelto-rivaroxaban-anticoagulant-therapy-gains-fda-new-indications-and-risk-reduction-for-dvt-and-pe-while-in-use-for-atrial-fibrillation-increase-in-gastrointestinal-gi-bleeding-reported/

Venous Thromboembolism (VTE): Blood Clots in Leg and Lungs – No. 3 Cardiovascular Killer Globally – Is Leading Cause of Premature Death and Disability in Hospitals

https://pharmaceuticalintelligence.com/2014/10/13/venous-thromboembolism-vte-blood-clots-in-leg-and-lungs-no-3-cardiovascular-killer-globally-is-leading-cause-of-premature-death-and-disability-in-hospitals/

The Relation between Coagulation and Cancer affects Supportive Treatments

https://pharmaceuticalintelligence.com/2015/10/19/the-relation-between-coagulation-and-cancer-affects-supportive-treatments/

Read Full Post »

The presence of any Valvular Heart Disease (VHD) did not influence the comparison of Dabigatran [Pradaxa, Boehringer Ingelheim] with Warfarin

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Atherogenic Processes & Pathology, Atrial Fibrilation (a-Fib), Cardiac Pacing and Arrhythmias, Cardiac and Cardiovascular Surgical Procedures, Coagulation Therapy and Internal Bleeding, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Mitral Valve: Repair and Replacement, Origins of Cardiovascular Disease, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Valves & Tools, tagged , , , , , on August 16, 2016| Leave a Comment »

The presence of any Valvular Heart Disease (VHD) did not influence the comparison of Dabigatran [Pradaxa, Boehringer Ingelheim] with Warfarin

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 10/22/2018

Dabigatran (Pradaxa) was no better than aspirin for prevention of recurrent stroke among patients with an embolic stroke of undetermined source in the RE-SPECT ESUS trial reported at the World Stroke Congress.

 

Pradaxa® (dabigatran etexilate)
Clinical experience of Pradaxa® equates to over 9 million patient-years in all licensed indications worldwide. Pradaxa® has been in the market for more than ten years and is approved in over 100 countries.15
Currently approved indications for Pradaxa® are:16,17
  • Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and a risk factor for stroke
  • Primary prevention of venous thromboembolic events in patients undergoing elective total hip replacement surgery or total knee replacement surgery
  • Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and the prevention of recurrent DVT and recurrent PE in adults
Dabigatran, a direct thrombin inhibitor (DTI), was the first widely approved drug in a new generation of direct oral anticoagulants, available to target a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases.18,19,20
REFERENCES

16 Pradaxa® US Prescribing Information, 2018.
17 Pradaxa® European Summary of Product Characteristics, 2018.
18 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285–95.
19 Di Nisio M. et al. Direct thrombin inhibitors. N Engl J Med.2005;353:1028–40.
20 Stangier J. et al. Pharmacokinetic Profile of the Oral Direct Thrombin Inhibitor Dabigatran Etexilate in Healthy Volunteers and Patients Undergoing Total Hip Replacement. J Clin Pharmacol. 2005;45:555–63

SOURCE

https://www.boehringer-ingelheim.com/press-release/Results-from-two-Pradaxa-trials-to-be-presented-at-WSC

 

 

Event Rate and Outcome Risk, With vs Without Valvular Heart Disease

Outcome Valvular heart disease, event rate/y, % No valvular heart disease, event rate/y, % HR (95% CI)* P
Stroke, systemic embolic event 1.61 1.41 1.09 (0.88–1.33) 0.43
Major bleeding 4.36 2.84 1.32 (1.16–1.33) <0.001
Intracranial hemorrhage 0.51 0.41 1.20 (0.83–1.74) 0.32
All-cause mortality 4.45 3.67 1.09 (0.96–1.23) 0.18
*Adjusted using propensity scores

ORIGINAL RESEARCH ARTICLE

Comparison of Dabigatran versus Warfarin in Patients with Atrial Fibrillation and Valvular Heart Disease: The RE-LY Trial

Michael D. Ezekowitz, Rangadham Nagarakanti, Herbert Noack, Martina Brueckmann, Claire Litherland, Mark Jacobs, Andreas Clemens,Paul A. Reilly, Stuart J. Connolly, Salim Yusuf and Lars Wallentin

 http://dx.doi.org/10.1161/CIRCULATIONAHA.115.020950

 

Results—There were 3950 patients with any VHD:

  • 3101 had mitral regurgitation,
  • 1179 tricuspid regurgitation,
  • 817 aortic regurgitations,
  • 471 aortic stenosis and
  • 193 mild mitral stenosis.

At baseline patients with any VHD had more

  • heart failure,
  • coronary disease,
  • renal impairment and
  • persistent atrial fibrillation.

Patients with any VHD had higher rates of

  • major bleeds (HR 1.32; 95% CI 1.16-1.5)

but similar

  • stroke or systemic embolism (SEE) rates (HR 1.09; 95% CI 0.88-1.33).

For D110 patients, major bleed rates were lower than warfarin (HR 0.73; 95% CI 0.56-0.95 with and HR 0.84; 95% CI 0.71-0.99 without VHD) and

For D150 similar to warfarin in patients with (HR 0.82; 95% CI 0.64-1.06) or without VHD (HR 0.98; 95% CI 0.83-1.15).

For D150 patients stroke/SEE rates were lower versus warfarin with (HR 0.59; 95% CI 0.37-0.93) and without VHD (HR 0.67; 95% CI 0.52-0.86) and similar to warfarin for D110 irrespective of presence of VHD (HR 0.97 CI 0.65-1.45 and 0.85 CI 0.70-1.10).

For intracranial bleeds and death rates for D150 and D110 were lower vs warfarin independent of presence of VHD.

Conclusions—The presence of any VHD did not influence the comparison of dabigatran with warfarin.

Clinical Trial Registration—URL: http://clinicaltrials.gov. Unique Identifier: NCT00262600.

SOURCES

http://circ.ahajournals.org/content/early/2016/08/05/CIRCULATIONAHA.115.020950

http://www.medscape.com/viewarticle/867482?nlid=108872_3866&src=WNL_mdplsfeat_160816_mscpedit_card&uac=93761AJ&spon=2&impID=1179558&faf=1

 

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