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Spleen Tyrosine Kinase Activation Drives Platelet Procoagulation in Antiphospholipid Syndrome During Pregnancy

E. Agbani1, S. Chaturvedi2, A. Lee3, P. Schneider4, M. Barber4, L. Yamaura4, K. Main4, Y. Eslambolchi4, A. Garven4, E. Mahe5, A. Dufour4, A. Clarke4, M. Choi4, M. Poon4, A. Poole6, L. Skeith4

1University of Calgary, CALGARY, Alberta, Canada, 2Johns Hopkins University, Baltimore, Maryland, United States, 3University of Victoria, Victoria, British Columbia, Canada, 4University of Calgary, Calgary, Alberta, Canada, 5University of Calgary, University of Calgary, Alberta, Canada, 6University of Bristol, Bristol, England, United Kingdom

Abstract Number: OC 51.4

Meeting: ISTH 2022 Congress

Theme: Women’s Health » Pregnancy and Pregnancy Complications

Background: Pregnant patients with antiphospholipid syndrome (APS) develop thrombotic and obstetric complications despite therapy with low-molecular-weight heparin (LMWH) and aspirin. Platelets are known to play a role in thrombosis, but platelet characteristics in pregnant patients with APS are poorly understood. Elucidating platelet procoagulant mechanisms may allow us to identify novel drug targets to improve thrombotic or obstetric outcomes.

Aims: To elucidate platelet characteristics and procoagulant mechanisms in pregnant patients with APS.

Methods: Two pregnant patients with systemic lupus erythematosus and high-titre triple positive antiphospholipid syndrome (APS/SLE) on LMWH/aspirin, and two pregnant control (PC) participants were followed at matched time points during pregnancy (REB19-1447). We utilized a high-resolution fluorescence imaging suite to visualise platelets in plasma, followed by a systematic analysis of procoagulant membrane dynamics and biochemical study.

Results: Circulating ballooned platelets typified all three trimesters of pregnancy in APS/SLE participants. Platelet activation and P-selectin expression increased as pregnancy progressed and peaked during gestational week 24-28. Expectedly, phosphatidylserine (PS) externalisation (indicated by platelet membrane annexin-V binding) and thrombin generation followed a similar temporal pattern. Additionally, PC platelets treated with plasma from APS/SLE participants (PC+) phenocopied the ballooning and procoagulation characteristics of APS/SLE platelets. Compared to PC platelets, APS/SLE platelets during the early 3rd trimester showed a four- to six-fold increase in Spleen tyrosine kinase (Syk) phosphorylation (Tyr-525/Tyr-526) and a three-fold increase in αIIbβ3 integrin activation. PC+ platelets also showed increased Syk phosphorylation but not integrin αIIbβ3 activation. Treatment of APS/SLE or PC+ platelets with the Syk inhibitor PRT-060318 (10 µM) significantly attenuated Syk phosphorylation, P-selectin expression, and PS exposure. Notably, PRT-060318 reduced αIIbβ3 integrin activation in APS/SLE platelets only, and inhibited membrane ballooning in PC+ but not APS/SLE platelets.

Conclusion(s): We provide evidence that Syk-driven platelet activation and procoagulation characterise pregnancy in APS/SLE patients. We are currently evaluating the mechanisms of antiphospholipid-driven platelet activation and procoagulation.

To cite this abstract in AMA style:

Agbani E, Chaturvedi S, Lee A, Schneider P, Barber M, Yamaura L, Main K, Eslambolchi Y, Garven A, Mahe E, Dufour A, Clarke A, Choi M, Poon M, Poole A, Skeith L. Spleen Tyrosine Kinase Activation Drives Platelet Procoagulation in Antiphospholipid Syndrome During Pregnancy [abstract]. https://abstracts.isth.org/abstract/spleen-tyrosine-kinase-activation-drives-platelet-procoagulation-in-antiphospholipid-syndrome-during-pregnancy/. Accessed August 16, 2022.

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