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B-cell response and thrombotic complications in COVID-19

Award Number: R01HL161127
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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B-cell response and thrombotic complications in COVID-19 - Abstract COVID-19 severity/lethality is associated with a dysfunctional inflammatory immune response and a hyper- engagement of pathways driving hemostasis and thrombosis, but the link between the two manifestations is not understood. Compared to patients with mild symptoms, severe COVID-19 patients have stronger IgG reactivity to SARS-CoV-2 virus and its spike protein receptor binding domain (RBD) and a robust B-cell response with a marked increase of the CD11c+CD21- B cells and plasmablast compartments. The incidence of thrombosis and inflammatory disease in severe COVID-19 is unprecedented, manifested by increased plasma inflammatory markers, such as IL-6, tumor necrosis factor alpha, C-reactive protein, and activation of compliment pathway etc., and dysregulated activation of cellular components participating in inflammatory and coagulation responses that include platelets, endothelial, monocytes, and neutrophils. The thrombotic manifestation ranges from arterial, venous, and tissue micro thrombosis to thromboembolism and is predominated by venous thromboembolism. Similar manifestations are observed in catastrophic thrombosis associated with heparin- induced thrombocytopenia and thrombosis (HIT). Patients with catastrophic HIT have the sudden onset of multiple arterial and venous thrombi with, but sometime without, heparin exposure, due to prothrombotic platelet- activating IgGs that recognize platelet factor 4 complexed with heparin polysaccharide (PF4/H). Using methods employed in previous studies of HIT, we studied patients with severe COVID-19 patients and identified PF4/H- reactive, pro-thrombotic IgG antibodies that closely resemble pathogenic antibodies found in patients with HIT in their ability to activate platelets. Surprisingly, levels of PF4/H antibodies in the patient plasma correlated with levels of antibodies specific for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. We cloned RBD-specific antibodies that are able to activate platelets. Compared to those that recognize RBD alone, significantly more B cells recognizing both RBD and PF4/H were CD11c+, CD21- and CXCR3+, which mark a subset of extrafollicular B cells robustly expanded in severe COVID-19. Based on these findings, we hypothesize that SARS-CoV-2 infection drives a subset of RBD-specific B cells to respond via an extrafollicular pathway and generate platelet-activating antibodies that contribute to thrombotic complications but not virus neutralization in severe COVID-19. To test our hypothesis, we will 1) investigate the prothrombotic activity of RBD-specific antibodies in the plasma of hospitalized COVID-19 patients; 2) investigate the expansion of B cells that make RBD-specific platelet-activating antibodies in severe COVID-19; 3) investigate the developmental pathway that governs affinity maturation of RBD and PF4/H cross-reactive B cells. Our proposal studies a novel B-cell/platelet axis in thrombotic complications in COVID-19 and should unravel a large portion of the complex pathogenesis of morbidity/mortality in this disease and suggest new treatment.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	VERSITI BLOOD HEALTH, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	4	11/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $659,871 )
2025	2025	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	4	9/19/2025	NON-COMPETING CONTINUATION	$65,986
2025	2025	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	4	3/4/2025	NON-COMPETING CONTINUATION	$593,885
														Subtotal = $659,871

Issue Date FY: 2024 ( Subtotal = $646,675 )
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	3	2/7/2024	NON-COMPETING CONTINUATION	$593,885
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	3	6/21/2024	NON-COMPETING CONTINUATION	$52,790
														Subtotal = $646,675

Issue Date FY: 2023 ( Subtotal = $659,871 )
2023	2023	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	2	2/22/2023	NON-COMPETING CONTINUATION	$659,871
														Subtotal = $659,871

Issue Date FY: 2022 ( Subtotal = $659,871 )
2022	2022	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	1	1/18/2022	NEW	$659,871
2022	2022	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	1	2/2/2022	NEW	$0
														Subtotal = $659,871

Grand Total All Awards = $2,626,288

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B-cell response and thrombotic complications in COVID-19

Award Number: R01HL161127

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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