TY - JOUR
T1 - Calprotectin Impairs Platelet Survival in Patients With Primary Antiphospholipid Syndrome
AU - Hoy, Claire K.
AU - NaveenKumar, Somanathapura K.
AU - Navaz, Sherwin A.
AU - Sugur, Kavya
AU - Yalavarthi, Srilakshmi
AU - Sarosh, Cyrus
AU - Smith, Tristin
AU - Kmetova, Katarina
AU - Chong, Emily
AU - Peters, Noah F.
AU - Rysenga, Christine E.
AU - Norman, Gary L.
AU - Figueroa-Parra, Gabriel
AU - Nelson, Dava
AU - Girard, Jennifer
AU - Ahmed, Asra Z.
AU - Schaefer, Jordan K.
AU - Gudjonsson, Johann E.
AU - Kahlenberg, J. Michelle
AU - Madison, Jacqueline A.
AU - Knight, Jason S.
AU - Crowson, Cynthia S.
AU - Duarte-García, Alí
AU - Zuo, Yu
N1 - Publisher Copyright:
© 2024 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.
PY - 2024
Y1 - 2024
N2 - Objective: While thrombosis and pregnancy loss are the best-known clinical features of antiphospholipid syndrome (APS), many patients also exhibit “extra-criteria” manifestations, such as thrombocytopenia. The mechanisms that drive APS thrombocytopenia are not completely understood, and no clinical biomarkers are available for predicting antiphospholipid antibody (aPL)–mediated thrombocytopenia. Calprotectin is a heterodimer of S100A8 and S100A9 that is abundant in the neutrophil cytoplasm and released upon proinflammatory neutrophil activation. Here, we sought to evaluate the presence, clinical associations, and potential mechanistic roles of circulating calprotectin in a cohort of primary APS and aPL-positive patients. Methods: Levels of circulating calprotectin were determined in plasma by the QUANTA Flash chemiluminescent assay. A viability dye-based platelet assay was used to assess the potential impact of calprotectin on aPL-mediated thrombocytopenia. Results: Circulating calprotectin was measured in 112 patients with primary APS and 30 aPL-positive (without APS criteria manifestations or lupus) patients as compared to patients with lupus (without APS), patients with unprovoked venous thrombosis (without aPL), and healthy controls. Levels of calprotectin were higher in patients with primary APS and aPL-positive patients compared to healthy controls. After adjustment for age and sex, calprotectin level correlated positively with absolute neutrophil count (r = 0.41, P < 0.001), positively with C-reactive protein level (r = 0.34, P = 0.002), and negatively with platelet count (r = −0.24, P = 0.004). Mechanistically, we found that calprotectin provoked aPL-mediated thrombocytopenia by engaging platelet surface toll-like receptor 4 and activating the NLRP3-inflammasome, thereby reducing platelet viability in a caspase-1-dependent manner. Conclusion: These data suggest that calprotectin has the potential to be a functional biomarker and a new therapeutic target for APS thrombocytopenia. (Figure presented.).
AB - Objective: While thrombosis and pregnancy loss are the best-known clinical features of antiphospholipid syndrome (APS), many patients also exhibit “extra-criteria” manifestations, such as thrombocytopenia. The mechanisms that drive APS thrombocytopenia are not completely understood, and no clinical biomarkers are available for predicting antiphospholipid antibody (aPL)–mediated thrombocytopenia. Calprotectin is a heterodimer of S100A8 and S100A9 that is abundant in the neutrophil cytoplasm and released upon proinflammatory neutrophil activation. Here, we sought to evaluate the presence, clinical associations, and potential mechanistic roles of circulating calprotectin in a cohort of primary APS and aPL-positive patients. Methods: Levels of circulating calprotectin were determined in plasma by the QUANTA Flash chemiluminescent assay. A viability dye-based platelet assay was used to assess the potential impact of calprotectin on aPL-mediated thrombocytopenia. Results: Circulating calprotectin was measured in 112 patients with primary APS and 30 aPL-positive (without APS criteria manifestations or lupus) patients as compared to patients with lupus (without APS), patients with unprovoked venous thrombosis (without aPL), and healthy controls. Levels of calprotectin were higher in patients with primary APS and aPL-positive patients compared to healthy controls. After adjustment for age and sex, calprotectin level correlated positively with absolute neutrophil count (r = 0.41, P < 0.001), positively with C-reactive protein level (r = 0.34, P = 0.002), and negatively with platelet count (r = −0.24, P = 0.004). Mechanistically, we found that calprotectin provoked aPL-mediated thrombocytopenia by engaging platelet surface toll-like receptor 4 and activating the NLRP3-inflammasome, thereby reducing platelet viability in a caspase-1-dependent manner. Conclusion: These data suggest that calprotectin has the potential to be a functional biomarker and a new therapeutic target for APS thrombocytopenia. (Figure presented.).
UR - http://www.scopus.com/inward/record.url?scp=85188417018&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85188417018&partnerID=8YFLogxK
U2 - 10.1002/art.42801
DO - 10.1002/art.42801
M3 - Article
C2 - 38225923
AN - SCOPUS:85188417018
SN - 2326-5191
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
ER -