Thromb Haemost
DOI: 10.1055/a-2510-6147
Blood Cells, Inflammation and Infection

Association of Specific Antiphospholipid Antibodies to Platelet Count and Thrombocytopenia

Katharina Griem
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany
,
Tanja Falter
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany
,
Anne Hollerbach
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany
,
2   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
,
Brahim Aboulmaouahib
3   Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center Mainz, Mainz, Germany
,
Julia Weinmann-Menke
4   Department of Medicine I, University Medical Center Mainz, Mainz, Germany
,
Nadine Müller-Calleja
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany
2   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
,
Karl J. Lackner
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany
› Author Affiliations
Funding This study was supported in part by the German Federal Ministry of Education and Research (BMBF 01EO1003).


Abstract

Background Thrombocytopenia is one of the most common manifestations of the antiphospholipid syndrome (APS). However, its causes are still poorly defined. We have shown recently that antiphospholipid antibodies (aPL) directed against β2-glycoprotein I (β2GPI) of the IgG isotype induced platelet activation and aggregation while aPL directed against cardiolipin and anti-β2GPI IgM had no effect. Since platelet activation by anti-β2GPI might lead to platelet consumption and lower platelet count or overt thrombocytopenia, we analyzed the association of aPL with platelet count.

Material and Methods Data of consecutive patients with test orders for anticardiolipin IgG/IgM and anti-β2GPI IgG/IgM and full blood count in our laboratory from August 2015 to April 2019 were analyzed.

Results We identified 2,815 individual patients (mean age 45.7 years; 71.1% women) with complete data on aPL and platelet count, of which 445 individuals (mean age 41.0 years; 75.3% women) showed increased aPL titers. Patients with anti-β2GPI of the IgG isotype had significantly lower platelet count (220 ± 84 versus 264 ± 90 G/L, p < 0.0001) and higher frequency of thrombocytopenia (platelet count <100 G/L; 12.2% versus 2.4%, p < 0.005) than patients negative for all four aPL. These differences could not be explained by comorbidities or medications. Neither anticardiolipin IgG nor aPL of the IgM isotype was associated with lower platelet count or thrombocytopenia.

Conclusion The exclusive association of anti-β2GPI IgG aPL with low platelet count coincides with its unique ability to activate platelets and induce aggregation in vitro. This supports the hypothesis that anti-β2GPI IgG aPL may induce thrombocytopenia by chronic platelet consumption in vivo.

Authors' Contribution

K.G. included data from medical documentation, reviewed the data, and wrote the manuscript (medical dissertation); J.W.M. provided critical patient data; B.A. reviewed the statistics; A.H. reviewed the data and wrote the manuscript; T.F., J.W.M., N.M.-C., and K.J. reviewed the data and the manuscript; K.J.L. designed the study, reviewed the data, and wrote the manuscript. The authors are responsible for the contents of this publication.


Supplementary Material



Publication History

Received: 13 August 2024

Accepted: 06 January 2025

Accepted Manuscript online:
07 January 2025

Article published online:
27 January 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 
  • References

  • 1 Cervera R, Serrano R, Pons-Estel GJ. et al; Euro-Phospholipid Project Group (European Forum on Antiphospholipid Antibodies). Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2015; 74 (06) 1011-1018
  • 2 Barbhaiya M, Zuily S, Naden R. et al; ACR/EULAR APS Classification Criteria Collaborators. 2023 ACR/EULAR antiphospholipid syndrome classification criteria. Ann Rheum Dis 2023; 82 (10) 1258-1270
  • 3 Schreiber K, Sciascia S, de Groot PG. et al. Antiphospholipid syndrome. Nat Rev Dis Primers 2018; 4: 17103
  • 4 Artim-Esen B, Diz-Küçükkaya R, İnanç M.. The significance and management of thrombocytopenia in antiphospholipid syndrome. Curr Rheumatol Rep 2015; 17 (03) 14
  • 5 Vreede AP, Bockenstedt PL, McCune WJ, Knight JS. Cryptic conspirators: a conversation about thrombocytopenia and antiphospholipid syndrome. Curr Opin Rheumatol 2019; 31 (03) 231-240
  • 6 Miyakis S, Lockshin MD, Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4 (02) 295-306
  • 7 Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 2011; 7 (06) 330-339
  • 8 de Groot PG. The antiphospholipid syndrome finally fathomed?. Blood 2018; 131 (19) 2091-2092
  • 9 Redecha P, Tilley R, Tencati M. et al. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury. Blood 2007; 110 (07) 2423-2431
  • 10 Prinz N, Clemens N, Strand D. et al. Antiphospholipid antibodies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells. Blood 2011; 118 (08) 2322-2332
  • 11 Prinz N, Clemens N, Canisius A. et al. Lessons from the antiphospholipid syndrome. Endosomal NADPH-oxidase is critical for induction of the tissue factor gene in monocytes and endothelial cells. Thromb Haemost 2013; 109: 525-531
  • 12 Manukyan D, Müller-Calleja N, Jäckel S. et al. Cofactor-independent human antiphospholipid antibodies induce venous thrombosis in mice. J Thromb Haemost 2016; 14 (05) 1011-1020
  • 13 Müller-Calleja N, Ritter S, Hollerbach A, Falter T, Lackner KJ, Ruf W. Complement C5 but not C3 is expendable for tissue factor activation by cofactor-independent antiphospholipid antibodies. Blood Adv 2018; 2 (09) 979-986
  • 14 Lackner KJ, Müller-Calleja N. Pathogenesis of the antiphospholipid syndrome revisited: time to challenge the dogma. J Thromb Haemost 2016; 14 (06) 1117-1120
  • 15 Müller-Calleja N, Köhler A, Siebald B. et al. Cofactor-independent antiphospholipid antibodies activate the NLRP3-inflammasome via endosomal NADPH-oxidase: implications for the antiphospholipid syndrome. Thromb Haemost 2015; 113 (05) 1071-1083
  • 16 Müller-Calleja N, Hollerbach A, Royce J. et al. Lipid presentation by the protein C receptor links coagulation with autoimmunity. Science 2021; 371 (6534) eabc0956
  • 17 Müller-Calleja N, Hollerbach A, Häuser F. et al. Antiphospholipid antibody induced cellular responses depend on epitope specificity—implications for treatment of APS. J Thromb Haemost 2017; 15: 2367-2376
  • 18 Hollerbach A, Müller-Calleja N, Ritter S. et al. Platelet activation by antiphospholipid antibodies depends on epitope specificity and is prevented by mTOR inhibitors. Thromb Haemost 2019; 119 (07) 1147-1153
  • 19 Manukyan D, Rossmann H, Schulz A. et al. Distribution of antiphospholipid antibodies in a large population-based German cohort. Clin Chem Lab Med 2016; 54 (10) 1663-1670
  • 20 Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 1998; 17 (08) 857-872
  • 21 Urbanus RT, Derksen RH, de Groot PG. Platelets and the antiphospholipid syndrome. Lupus 2008; 17 (10) 888-894
  • 22 Baroni G, Banzato A, Bison E, Denas G, Zoppellaro G, Pengo V. The role of platelets in antiphospholipid syndrome. Platelets 2017; 28 (08) 762-766
  • 23 Fanelli A, Bergamini C, Rapi S. et al. Flow cytometric detection of circulating activated platelets in primary antiphospholipid syndrome. Correlation with thrombocytopenia and anticardiolipin antibodies. Lupus 1997; 6 (03) 261-267
  • 24 Wiener MH, Burke M, Fried M, Yust I. Thromboagglutination by anticardiolipin antibody complex in the antiphospholipid syndrome: a possible mechanism of immune-mediated thrombosis. Thromb Res 2001; 103 (03) 193-199
  • 25 Müller-Calleja N, Ruf W, Lackner KJ. Lipid-binding antiphospholipid antibodies: significance for pathophysiology and diagnosis of the antiphospholipid syndrome. Crit Rev Clin Lab Sci 2024; 61 (05) 370-387