Skip to main content

Reimagining the antiphospholipid syndrome, an enigmatic thrombophilic disorder, through the looking glass of microscopic imaging

Histochemistry and Cell Biology volume 150, pages 529–543 (2018)Cite this article

Abstract

The antiphospholipid syndrome (APS) is an autoimmune thrombophilic disorder that was described as a diagnostic entity over 30 years ago. And yet the pathogenic mechanisms that are responsible for its clinical manifestations remain to be definitively established. The syndrome is defined by (1) the concurrence of vascular thrombosis and/or pregnancy complications together with (2) positivity for immunoassays and coagulation tests that were derived from clinical observations of two anomalous laboratory test results—specifically, false positivity for syphilis infection in uninfected individuals and the finding of inhibitors of blood coagulation in patients who lacked any bleeding tendencies. Over the years, these were standardized into immunoassays and coagulation assays for APS. Here, we describe how prior knowledge of the immunologic and coagulation aspects of the disorder led to research involving a range of imaging modalities including light microscopy, immunohistochemistry, confocal scanning laser microscopy, transmission and scanning electron microscopy, and atomic force microscopy. In turn, the results from those studies led to a “reimagining” of APS that has advanced the understanding of pathogenic mechanisms of the disorder and has led to the development of novel mechanistically based diagnostics along with potential new treatment approaches that target disease mechanisms.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1

(From Krikun et al. 1994)

Fig. 2

(Modified from Wu et al. 2011)

Fig. 3

(From Rand et al. 1998)

Fig. 4

Drawing modified from original published in Taatjes et al. (2013)

Fig. 5

(From Rand et al. 2003)

Fig. 6

(From Rand 2010)

Fig. 7

(From Rand et al. 2008)

Fig. 8

(From Rand et al. 2010b)

Fig. 9

Images originally published in Taatjes et al. (2014)

Fig. 10

[Images originally published in Taatjes et al. (2014)]

Fig. 11

Figure modified from original version published in Taatjes et al. (2017)

Fig. 12

Figure modified from original version published in Taatjes et al. (2017)

Fig. 13

(From Rand et al. 2017)

References

  • Bezati E, Wu XX, Quinn AS, Taatjes DJ, Rand JH (2015) A new trick for an ancient drug: quinine dissociates antiphospholipid immune complexes. Lupus 24:32–41

    Article  CAS  Google Scholar 

  • Binnig C, Quate CF, Gerber CH (1986) Atomic force microscope. Phys Rev Lett 56:930–933

    Article  CAS  Google Scholar 

  • Braet F, Taatjes DJ (2018) Foreword to the special issue on applications of atomic force microscopy in cell biology. Sem Cell Dev Biol 73:1–3

    Article  Google Scholar 

  • Conley CL, Hartmann RC (1952) A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematousus. J Clin Invest 31:621

    Google Scholar 

  • Edwards MH, Pierangeli S, Liu X, Barker JH, Anderson G, Harris EN (1997) Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation 96:4380–4384

    Article  CAS  Google Scholar 

  • Erkan D, Yazici Y, Peterson MG, Sammaritano L, Lockshin MD (2002) A cross-sectional study of clinical thrombotic risk factors and preventative treatments in antiphospholipid syndrome. Rheumatology 41:924–929

    Article  CAS  Google Scholar 

  • Feinstein DI, Rapaport SI (1972) Acquired inhibitors of blood coagulation. In: Spaet TH (ed) Progress in hemostasis and thrombosis, 1 edn. Grune & Stratton, New York, pp 75–95

    Google Scholar 

  • Gamsjaeger R, Johs A, Gries A, Gruber HJ, Romsnin C, Hinterdorfer P (2005) Membrane binding of βGPI can be described by a two-state reaction model: an atomic force microscopy and surface plasmon resonance study. Biochem J 389:665–673

    Article  CAS  Google Scholar 

  • Glassie J (2012) A man of misconceptions: the life of an eccentric in an age of change. Riverhead Books, New York

    Google Scholar 

  • Harris EN, Gharavi AE, Boey ML et al (1983) Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 2:1211–1214

    Article  CAS  Google Scholar 

  • Hughes GR (1985) The anticardiolipin syndrome. Clin Exp Rheumatol 3:285–286

    CAS  PubMed  Google Scholar 

  • Hunt JE, McNeil HP, Morgan GJ, Crameri RM, Krilis SA (1992) A phospholipid-beta 2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection. Lupus 1:75–81

    Article  CAS  Google Scholar 

  • Jones JV, James H, Tan MH, Mansour M (1992) Antiphospholipid antibodies require beta 2-glycoprotein I (apolipoprotein H) as cofactor. J Rheumatol 19:1397–1402

    CAS  PubMed  Google Scholar 

  • Katan AJ, Dekker C (2011) High-speed AFM reveals the dynamics of single biomolecules at the nanometer scale. Cell 147:979–982

    Article  CAS  Google Scholar 

  • Krikun G, Lockwood CJ, Wu XX, Zhou XD, Guller S, Calandri C, Guha A, Namerson Y, Rand JH (1994) The expression of the placental anticoagulant protein, annexin V, by villous trophoblasts: immunolocalization and in vitro regulation. Placenta 15:601–612

    Article  CAS  Google Scholar 

  • Lembke A, Ruska H (1940) Vergleichende mikroskopische und übermikroskopische  Beobachtung an den Erregern der Tuberkulose (Comparative optical and electron microscopical observation into the causative agents of tuberculosis). Klin Wochenschr 19:217–220

    Article  Google Scholar 

  • Lubinski HH (1947) Interpretation and significance of false positive serologic reactions for syphilis. Can Med Assoc 57:33–35

    Google Scholar 

  • Miyakis S, Lockshin MD, Atsumi T et al (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Hemost 4:295–306

    Article  CAS  Google Scholar 

  • Montigny WJ, Quinn AS, Wu XX, Bovill EG, Rand JH, Taatjes DJ (2006) Atomic force microscopy in the study of macromolecular interactions in hemostasis and thrombosis. Utility for investigation of the antiphospholipid syndrome. In: Jena BP, Horber KH (eds) Force microscopy: applications in biology and medicine. Wiley, Hoboken, pp 267–286

    Chapter  Google Scholar 

  • Moss SE (1997) Annexins. Trend Cell Biol 7(3):87–89

    Article  CAS  Google Scholar 

  • O’Neill KT, Hoess RH, Jackson SA, Ramachandran NS, Mousa SA, DeGrado WF (1992) Identification of novel peptide antagonists for GPIIb/IIIa from a confirmation ally constrained phage peptide library. Proteins 14:509–515

    Article  Google Scholar 

  • Oosting JD, Derksen RH, Entjes HT, Bouma BN, de Groot PG (1992) Lupus anticoagulant activity is frequently dependent on the presence of beta 2-glycoprotein I. Thromb Haemost 67:499–502

    Article  CAS  Google Scholar 

  • Pengo V, Tripodi A, Reber G et al (2009) Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. J Thromb Haemost 7:1737–1740

    Article  CAS  Google Scholar 

  • Petri M (1996) Hydroxychloroquine use in the Baltimore Lupus Cohort: effects on lipids, glucose and thrombosis. Lupus 5(Suppl 1):S16–S22

    CAS  Google Scholar 

  • Quinn AS, Rand JH, Wu X-X, Taatjes DJ (2012a) Viewing dynamic interactions of proteins and a model lipid membrane with atomic force microscopy. In: Taatjes DJ, Roth J (eds) Cell imaging techniques: methods and protocols, methods in molecular biology, vol 931. Springer Science + Business Media, New York, pp 259–293

    Chapter  Google Scholar 

  • Quinn AS, Wu X-X, Rand JH, Taatjes DJ (2012b) Insights into the pathophysiology of the antiphospholipid syndrome provided by atomic force microscopy. Micron 43:851–862

    Article  CAS  Google Scholar 

  • Rand JH (2010) The antiphospholipid syndrome. In: Kaushansky K, Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Prchal JT (eds) Williams’ hematology, 8/E edn. McGraw-Hill, New York, pp 2145–2161 2010

    Google Scholar 

  • Rand JH, Wu XX, Guller S, Gil J, Guha A, Scher J, Lockwood CJ (1994) Reduction of annexin-V (placental anticoagulant protein-1) on placental villi of women with antiphospholipid antibodies and recurrent spontaneous abortion. Am J Obstet Gynecol 171:1566–1572

    Article  CAS  Google Scholar 

  • Rand JH, Wu XX, Andree HA, Lockwood CJ, Guller S, Scher J, Harpel PC (1997) Pregnancy loss in the antiphospholipid-antibody syndrome—a possible thrombogenic mechanism. New Engl J Med 337:154–160

    Article  CAS  Google Scholar 

  • Rand JH, Wu XX, Andree HA, Ross JB, Rusinova E, Gascon-Lema MG, Calandri C, Harpel PC (1998) Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: a “lupus procoagulant” phenomenon. Blood 92:1652–1660

    CAS  PubMed  Google Scholar 

  • Rand JH, Wu XX, Quinn AS, Chen PP, McCrae KR, Bovill EG, Taatjes DJ (2003) Human monoclonal antiphospholipid antibodies disrupt the annexin A5 anticoagulant crystal shield on phospholipid bilayers: evidence from atomic force microscopy and functional assay. Am J Pathol 163:1193–1200

    Article  CAS  Google Scholar 

  • Rand JH, Wu XX, Lapinski R, van Heerde WL, Reutelingsperger CP, Chen PP, Ortel TL (2004) Detection of antibody-mediated reduction of annexin A5 anticoagulant activity in plasmas of patients with the antiphospholipid syndrome. Blood 104:2783–2790

    Article  CAS  Google Scholar 

  • Rand JH, Wu XX, Quinn AS, Chen PP, Hathcock JJ, Taatjes DJ (2008) Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-beta2-glycoprotein I complexes to phospholipid bilayers. Blood 112:1687–1695

    Article  CAS  Google Scholar 

  • Rand JH, Wu X-X, Quinn AS, Taatjes DJ (2010a) The annexin A5-mediated pathogenic mechanism in the antiphospholipid syndrome: role in pregnancy losses and thrombosis. Lupus 19:460–469

    Article  CAS  Google Scholar 

  • Rand JH, Wu XX, Quinn AS, Ashton AW, Chen PP, Hathcock JJ, Andree HAM, Taatjes DJ (2010b) Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug. Blood 115:2292–2299

    Article  CAS  Google Scholar 

  • Rand JH, Wu XX, Wolgast LR, Lei V, Conway EM (2017) A novel 2-stage approach that detects complement activation in patients with antiphospholipid antibody syndrome. Thromb Res 156:119–125

    Article  CAS  Google Scholar 

  • Reviakine I, Bergsma-Schutter W, Mazeres-Dubut C, Govorukhina N, Brisson A (2000) Surface topography of the p3 and p6 annexin V crystal forms determined by atomic force microscopy. J Struct Biol 131:234–239

    Article  CAS  Google Scholar 

  • Ruska E (1980) The early development of electron lenses and electron microscopy. S. Hirzel Verlag, Stuttgart

    Google Scholar 

  • Taatjes DJ, Quinn AS, Rand JH, Jena BP (2013) Atomic force microscopy: high resolution dynamic imaging of cellular and molecular structure in health and disease. J Cell Physiol 228:1949–1955

    Article  CAS  Google Scholar 

  • Taatjes DJ, Quinn AS, Wu X-X, Tsai H-M, Rand JH (2014) Repair of nanodefects in a 2-dimensional crystal anticoagulant shield in the antiphospholipid syndrome: Novel molecular strategies assessed by atomic force microscopy. In: Jena BP, Taatjes DJ (eds) NanoCellBiology—multimodal imaging in biology and medicine. Pan Stanford Ltd., Singapore, pp 157–171

    Chapter  Google Scholar 

  • Taatjes DJ, Bouffard N, von Turkovich M, Quinn AS, Wu X-X, Vasovic LV, Rand JH (2017) Visualization of macro-immune complexes in the antiphospholipid syndrome by multi-modal microscopy imaging. Micron 100:23–29

    Article  CAS  Google Scholar 

  • Ueki H, Mizushina T, Laoharatchatathanin T, Terashima R, Nishimura Y, Rieanrakwong D, Yonezawa T, Kurusu S, Hasegawa Y, Brachvogel B, Pöschl E, Kawaminami M (2012) Loss of maternal annexin A5 increases the likelihood of placental platelet thrombosis and foetal loss. Sci Rep 2:827. https://doi.org/10.1038/srep00827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vogt E, Ng AK, Rote NS (1997) Antiphosphatidylserine antibody removes annexin-V and facilitates the binding of prothrombin at the surface of a choriocarcinoma model of trophoblast differentiation. Am J Obstet Gynecol 177:964–972

    Article  CAS  Google Scholar 

  • Wang X, Campos B, Kaetzel MA, Dedman JR (1999) Annexin V is critical in the maintenance of murine placental integrity. Am J Obstet Gynecol 180(4):1008–1016

    Article  CAS  Google Scholar 

  • Wolgast LR, Arslan AA, Wu XX, Beyda JN, Pengo V, Rand JH (2017) Reduction of annexin A5 anticoagulant ratio identifies antiphospholipid antibody-positive patients with adverse clinical outcomes. J Thromb Haemost 15(7):1412–1421

    Article  CAS  Google Scholar 

  • Wu X-X, Guller S, Rand JH (2011) Hydroxychloroquine reduces binding of antiphospholipid antibodies to syncytiotrophoblasts and restores annexin A5 expression. Am J Obstet Gynecol 205:576 (e7–e14)

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

First, we express our gratitude to Dr. Edwin (“Ted”) Bovill who brought the authors together to initiate a long-standing and enriching research collaboration. We thank Nicole Bouffard, Anthony Quinn, and Michele von Turkovich for excellent technical assistance for the microscopic imaging portions of this manuscript, Dr. Xiao Xian Wu for her key roles in advancing this project, and Mr. Laurence A. Guerino for his office support in the preparation of this manuscript. The projects described were supported by Award number S10RR025498 from the National Center for Research Resources (DJT) for the purchase of the atomic force microscope.

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA

    Jacob H. Rand

  2. Department of Pathology and Laboratory Medicine, and Microscopy Imaging Center, Larner College of Medicine, University of Vermont, 89 Beaumont Avenue, Burlington, VT, 05405, USA

    Douglas J. Taatjes

Authors
  1. Jacob H. Rand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Douglas J. Taatjes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Douglas J. Taatjes.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rand, J.H., Taatjes, D.J. Reimagining the antiphospholipid syndrome, an enigmatic thrombophilic disorder, through the looking glass of microscopic imaging. Histochem Cell Biol 150, 529–543 (2018). https://doi.org/10.1007/s00418-018-1709-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-018-1709-2

Keywords

  • Antiphospholipid syndrome
  • Atomic force microscopy
  • Scanning electron microscopy
  • Confocal microscopy
  • Immunohistochemistry