PB1359 - Fc modified KKO blocks thrombosis in heparin-induced thrombocytopenia (HIT), but not in vaccine-induced immune thrombotic thrombocytopenia (VITT)

Tuesday, June 27, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

AS

Amrita Sarkar

Research Associate
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
Philadelphia, Pennsylvania, United States

Co-Author(s)

Anh T. Ngo, PhD

Postdoc
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
Philadelphia, Pennsylvania, United States
SK

Sanjay Khandelwal

Assistant Professor
Division of Hematology, Duke University Medical Center, Durham, NC
Durham, North Carolina, United States
Kandace Gollomp

Assistant Professor
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
Philadelphia, Pennsylvania, United States
GA

Gowthami M. Arepally, M.D.

professor
Division of Hematology, Duke University Medical Center, Durham, NC
Durham, North Carolina, United States
DB

Douglas B. B. Cines

professor
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
Philadelphia, Pennsylvania, United States
LR

Lubica Rauova, MD, PhD

Associate Professor
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
Philadelphia, Pennsylvania, United States
MP

Mortimer Poncz

Professor
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
Philadelphia, Pennsylvania, United States

Background: HIT and VITT are both associated with thrombocytopenia and thrombosis, but with antibodies directed against different antigenic sites on platelet factor 4 (PF4). HIT antibodies bind human (h) PF4:heparin complexes. KKO is a HIT-like mouse monoclonal antibody. Injection of KKO into mice expressing hPF4 and FcRIIA (termed HIT mice) results in thrombocytopenia and thrombosis. We deglycosylated the Fc region of KKO to generate DGKKO that competes with KKO for binding hPF4:heparin, does not activate platelets, and minimally activates complement.

Aims: Determine whether DGKKO can be used to block thrombocytopenia and thrombosis in models of HIT and VITT.

Methods: Microfluidics studies in human endothelial-lined channels were done using normal blood samples with added HIT and VITT IgGs (immunoglobulins) and observing for thrombus formation in the channels ± DGKKO intervention. HIT mice were injected with HIT IgG injection ± subsequent DGKKO rescue, and cremaster thrombus development following laser injury observed.

Results: Both KKO and HIT IgG added to whole blood resulted in thrombus formation in a microfluidic device. DGKKO inhibited thrombus formation (Figure 1A). Parallel studies with VITT IgG showed similar thrombus formation; however, DGKKO did not ameliorate the prothrombotic state (Figure 1B). Infusion of DGKKO rescued HIT mice from thrombocytopenia induced by HIT antibodies (Figure 2A), and reduced cremaster thrombus formation (Figure 2B).

Conclusion(s): DGKKO is protective against both the thrombocytopenic and thrombotic effects of HIT IgGs in a small number of tested patients, being the first agent to prevent thrombocytopenia and reduce thrombus size post-HIT antibody exposure. DGKKO was not similarly protective after VITT IgG consistent with the HIT and VITT antigenic sites being distinct. More samples of both HIT and VITT IgGs need to be tested, but our studies suggest that an Fc-modified KKO may be an effective therapeutic agent in HIT.