Platelet factor 4-centric immunothrombosis in the antiphospholipid syndrome Conroy O Field

Format:

Book

Thesis/Dissertation

Author/Creator:

Field, Conroy O., author.

Contributor:

University of Pennsylvania. Pharmacology., degree granting institution.

Language:

English

Subjects (All):

Pharmacology.

Biomedical engineering.

Clinical psychology.

Immunology.

0419.

0541.

0982.

0622.

Local Subjects:

Pharmacology.

Biomedical engineering.

Clinical psychology.

Immunology.

0419.

0541.

0982.

0622.

Genre:

Academic theses

Physical Description:

1 online resource (122 pages)

Contained In:

Dissertations Abstracts International 87-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2026

Language Note:

English

Summary:

Platelet factor 4 (PF4, CXCL4) is a highly abundant platelet-specific chemokine with important roles in immunothrombosis and represents a promising target for non-anticoagulant therapeutic development. A prototypical immunothrombotic disorder is the antiphospholipid syndrome (APS), which is often associated with autoantibodies that recognize the plasma protein β2-glycoprotein I (β2GPI, APOH). A prior study reported that these antibodies bind β2GPI more avidly in the presence of PF4. Both PF4 and β2GPI bind to neutrophil extracellular traps (NETs) extruded from activated neutrophils. We hypothesized that PF4 bridges β2GPI onto NETs to form an antigenic triplex that is central to thrombosis in APS. We used IgG-type antibodies isolated from triple-positive APS patients with thrombosis. Dynamic light scattering studies show that DNA, PF4, and β2GPI assembled into a large triplex that the APS antibodies selectively recognized. In a NET-lined microfluidic system, PF4 enhanced β2GPI binding to NETs, which increased APS antibody recognition and generated immune complexes that were more resistant to nuclease digestion and more efficient at capturing platelets. In a photochemically injured endothelial-lined microfluidic system, exogenous PF4 was necessary to induce robust platelet, fibrin, and complement deposition during APS-mediated in vitro thrombus formation. In vivo murine studies using a passive immunization APS model demonstrate that PF4 was required for enhanced neutrophil adhesiveness along the uninjured cremaster venous endothelium. Upon laser injury to the cremaster vessels post-APS induction, large platelet-rich thrombi developed in a PF4-dependent fashion. Neutrophil incorporation into the venular thrombi and neutrophil extracellular vesicle accumulation in the arteriolar thrombi were greater in transgenic mice expressing human (h) PF4 ± FcγRIIA than in their mouse PF4 knockout littermates. We tested three anti-hPF4 blocking monoclonal antibodies that target separate epitopes on hPF4 and show that each disrupted the APS immune complexes and attenuated thrombosis in vitro as well as neutrophil adhesiveness and thrombosis in vivo in APS. Collectively, these studies provide new mechanistic insights into the immunothrombotic processes underlying APS and introduce potential non-anticoagulant therapeutic strategies for its clinical management

Notes:

Source: Dissertations Abstracts International, Volume: 87-12, Section: B.

Advisors: Poncz, Mortimer Committee members: Muzykantov, Vladimir R.; Gollomp, Kandace L.; Abrams, Charles S.; Brenner, Jacob S.

Ph.D. University of Pennsylvania 2026

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798247973751

Access Restriction:

Restricted for use by site license