Neutrophil accumulation and NET release contribute to thrombosis in HIT

Gollomp, Kandace; Kim, Minna; Johnston, Ian; Hayes, Vincent; Welsh, John D.; Arepally, Gowthami M.; Kahn, Mark L.; Lambert, Michele P.; Cuker, Adam; Cines, Douglas B.; Rauova, Lubica; Kowalska, M. Anna; Poncz, Mortimer

doi:10.1172/jci.insight.99445

Cited by 129 publications

(183 citation statements)

References 60 publications

(78 reference statements)

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“…PF4 binds to and aggregates polyanions like heparin 26 . We and others have found that PF4 similarly aggregates NETs, physically compacting them, and enhancing their resistance to endogenous and microbial nucleases 27,28 . We speculated that this activity may be, in part, responsible for our previous observation that PF4 enhances survival in murine lipopolysaccharide (LPS) endotoxemia 29 .…”

Section: Introductionmentioning

confidence: 74%

“…The infusion of wild-type (WT) mice with platelets obtained from hPF4 + animals improved survival 29 . We have recently found that PF4 binds to NETs, leading them to become physically compact and DNase resistant 27 .…”

Section: The Effect Of Pf4 On Plasma Levels Of Ndps In Murine Endotoxmentioning

confidence: 99%

“…By the time most patients present with the symptoms of sepsis, their platelets have been have already been stimulated to release large amounts of PF4 25 , limiting the therapeutic benefit of infusing additional PF4. Our prior observation that the HIT-like monoclonal antibody KKO enhances DNase resistance of hPF4-NET complexes 27 raised the possibility that KKO may amplify the effect of endogenous PF4 and be of therapeutic benefit in sepsis. However, KKO fixes complement 33 , activates platelets 30 , and stimulates leukocytes 27,34 , inducing the development of a prothrombotic state in hPF4 + /FcRIIa-expressing mice 35 and increasing mortality in murine endotoxemia ( Figure 5D).…”

Section: Studies Of the In Vitro Effects Of Dg-kkomentioning

confidence: 99%

“…KKO is a monoclonal antibody directed against PF4-heparin complexes that induces thrombocytopenia and a prothrombotic state when injected into mice that express human (h) PF4 and FcRIIA, mimicking the clinical disorder of heparin-induced thrombocytopenia (HIT) 30 . KKO binds hPF4-NET complexes, further enhancing DNase resistance 27 . We speculated that treatment with an Fc-modified KKO that could not activate platelets via FcRIIa may augment the protective effect of PF4 in sepsis by stabilizing hPF4-NET complexes.…”

Section: Introductionmentioning

confidence: 99%

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Neutrophil extracellular trap stabilization leads to improved outcomes in murine models of sepsis

Gollomp

Sarkar

Seeholzer

et al. 2019

Preprint

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Word Count: 204 Text Word Count: 4622 Figure Count: 7 Reference Count: 81 AbstractSepsis is characterized by multi-organ system dysfunction that occurs due to infection. It is associated with unacceptably high morbidity and mortality and in need of improved therapeutic intervention. Neutrophils play a crucial role in sepsis, releasing neutrophil extracellular traps (NETs) composed of DNA complexed with histones and toxic antimicrobial proteins that ensnare pathogens but also damage host tissues. At presentation, patients likely have a significant NET burden contributing to the multi-organ damage. Therefore, interventions that prevent NET release would likely be ineffective at preventing NET-based injury. Treatments that enhance NET degradation may liberate captured bacteria and toxic NET degradation products (NDPs) and therefore be of limited therapeutic benefit. We propose that interventions that stabilize NETs and sequester NDPs may be protective in sepsis. Platelet factor 4 (PF4, CXCL4) a platelet-associated chemokine, binds and compacts NETs, increasing their resistance to deoxyribonuclease I. A monoclonal antibody, KKO, which binds to PF4-NET complexes, further enhances this resistance.We now show that PF4 increases NET-mediated bacterial capture in vitro, reduces the release of NDPs, and improves outcome in murine models of sepsis. An Fc-modified KKO further enhances deoxyribonuclease resistance, decreases NDP release, and increases survival in these models, supporting a novel NET-targeting approach to improve outcomes in sepsis.

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Section: Introductionmentioning

confidence: 74%

Section: The Effect Of Pf4 On Plasma Levels Of Ndps In Murine Endotoxmentioning

confidence: 99%

Section: Studies Of the In Vitro Effects Of Dg-kkomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neutrophil extracellular trap stabilization leads to improved outcomes in murine models of sepsis

Gollomp

Sarkar

Seeholzer

et al. 2019

Preprint

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“…Activated endothelium also releases von Willebrand factor, which binds PF4 and HIT antibodies, promotes platelet adhesion and additional PF4 release, creating a feed-forward prothrombotic pathway. 140 HIT immune complexes assembling on PF4 bound to GAGs expressed on monocytes signal through Fcγ receptors to stimulate production of thrombin that transactivates platelets in concert with their direct activation by HIT antibodies. Neutrophils activated by HIT antibodies adhere to venous endothelium, accumulate downstream of the evolving thrombus, and contribute to venous thrombosis at least partially through a peptidyl arginine deiminase 4 (PAD4)-dependent pathway.…”

Section: Neutrophilmentioning

confidence: 99%

Illustrated State‐of‐the‐Art Capsules of the ISTH 2019 Congress in Melbourne, Australia

Ward

Andrews

2019

Research and Practice in Thrombosis and Haemostasis

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The 27th Congress of the International Society of Thrombosis and Haemostasis (ISTH) is an international conference held July 6‐10, 2019, in Melbourne, the capital of the state of Victoria, Australia. The ISTH congress has previously been held every other year, with the Scientific and Standardization Committee (SSC) meeting held annually, until 2019 when it became one combined annual meeting of the ISTH and SSC. The conference covers clinical and basic aspects of hemostasis and thrombosis, and this year includes 5 Plenary lectures and >50 State of Art (SOA) lectures, presented by internationally recognized speakers, as well as numerous oral session and poster presentations selected from submitted abstracts, including many early career and reach the world support recipients. This SOA review article in RPTH contains concise Illustrated Review Articles or ‘Capsules’ consisting of short text, three references and a figure, with topics including stroke, cancer‐associated thrombosis, hemophilia, coagulation, the interface between infection and inflammation, and in the experimental and discovery areas, megakaryocyte biology and platelet production, structure‐function of key receptors and coagulation factors, and emerging new roles for thrombotic/hemostatic factors. Together, these articles highlight novel findings which will advance knowledge and with the potential to change clinical practice and improve outcomes. It is hoped that conference attendees and followers will enjoy utilizing the images for ongoing education and during the conference for live tweeting during sessions, to assist in the broadcasting and promotion of the science to those unable to attend, or who have chosen to attend a concurrent session. Use #IllustratedReview and #ISTH2019 on social media.

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Platelets accumulate in lung lesions of tuberculosis patients and inhibit T‐cell responses and Mycobacterium tuberculosis replication in macrophages

et al. 2022

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Platelets regulate human inflammatory responses that lead to disease. However, the role of platelets in tuberculosis (TB) pathogenesis is still unclear. Here, we show that patients with active TB have a high number of platelets in peripheral blood and a low number of lymphocytes leading to a high platelets to lymphocytes ratio (PL ratio). Moreover, the serum concentration of different mediators promoting platelet differentiation or associated with platelet activation is increased in active TB. Immunohistochemistry analysis shows that platelets localise around the lung granuloma lesions in close contact with T lymphocytes and macrophages. Transcriptomic analysis of caseous tissue of human pulmonary TB granulomas, followed by Gene Ontology analysis, shows that 53 platelet activation-associated genes are highly expressed compared to the normal lung tissue. In vitro activated platelets (or their supernatants) inhibit BCG-induced T-lymphocyte proliferation and IFN-γ production. Likewise, platelets inhibit the growth of intracellular macrophages ofMycobacterium (M.) tuberculosis. Soluble factors released by activated platelets mediate both immunological and M. tuberculosis replication activities. Furthermore, proteomic and neutralisation studies (by mAbs) identify TGF-β and PF4 as the factors responsible for inhibiting T-cell response and enhancing the mycobactericidal activity of macrophages, respectively. Altogether these results highlight the importance of platelets in TB pathogenesis.

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Neutrophil accumulation and NET release contribute to thrombosis in HIT

Cited by 129 publications

References 60 publications

Neutrophil extracellular trap stabilization leads to improved outcomes in murine models of sepsis

Neutrophil extracellular trap stabilization leads to improved outcomes in murine models of sepsis

Illustrated State‐of‐the‐Art Capsules of the ISTH 2019 Congress in Melbourne, Australia

Platelets accumulate in lung lesions of tuberculosis patients and inhibit T‐cell responses and Mycobacterium tuberculosis replication in macrophages

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