Human Reproduction, Vol. 18, No. 7, 1553-1554,
July 2003
© 2003 European Society of Human Reproduction and Embryology
Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique APA positive population
1 Department of Obstetrics and Gynecology, Tokai University School of Medicine, Kanagawa, Japan and 2 HLA Vascular Biology Laboratory, St. Francis Hospital and Health Centers Indianapolis, IN, USA
3 To whom correspondence should be addressed. e-mail: sugi{at}is.icc.u-tokai.ac.jp
Dear Sir,
We read the recent article by Franklin and Kutteh (2002
), concerning the pregnancy outcomes of recurrent pregnancy loss (RPL) patients who had normal obstetrical evaluations with the exception of positive antiphospholipid antibodies (aPL) findings. In their report distinctions were made between two groups of aPL positive RPL patients with reference to their aPL specificities. Group 1 patients had ‘the common’ aPL, anticardiolipin (aCL), or antiphosphatidylserine antibodies (aPS) and/or a lupus anticoagulant (LAC). For comparisons, Group 2 patients had aPL with specificities for phosphatidylinositol (aPI), phosphatidylglycerol (aPG) and/or phosphatidylethanolamine (aPE). Group 2 aPL patients were divided into two treatment groups, those treated with heparin and aspirin, as were the Group 1 patients, and those receiving aspirin only were defined as Group 3. The authors concluded that aPL, other than aCL, aPS and LAC, identified a population of women having similar prior risk for a miscarriage as those women with aCL, aPS and/or LAC.
As the authors rightly emphasize, the lack of standardization among APA laboratories has made it difficult and confusing for physicians to identify aPL-positive patients with certainty and clarity. However, from the information provided in the Materials and methods section, we are concerned that Franklin and Kutteh’s findings also are biased by technical procedures. For example, the authors use 10% fetal calf serum (FCS) to block the ELISA plate-wells, as well as in the patient serum diluents. This choice can negate the findings of aPL that are independent of phospholipid-binding plasma proteins. These independent aPL specificities, which also have been associated with RPL (Ozawa et al., 1994), might well be scored as false negatives because the phospholipid-binding plasma proteins in the FCS can block the plasma-protein independent aPL from binding (Matsuura et al., 1990; 1992). It is important to recall that plasma-protein independent aPL have been shown to bind directly to the human trophoblast in vitro; to inhibit trophoblast hCG production; to affect adversely trophoblast invasion into Matrigel substrates; to retard differentiation of cytotrophoblast into a syncytium (Katsuragawa et al., 1997; Di Simone et al., 2000) and to exert LAC activity (Gallart et al., 2002). Of further interest is the observation that heparin and low dose aspirin can partially abrogate these adverse aPL effects (Di Simone et al., 1997).
An additional concern exists with using FCS as a source of phospholipid-binding plasma proteins for detection of aPE. We reported that many aPE are dependent upon the phospholipid-binding kininogens for detection (Sugi and McIntyre, 1995). The source of kininogens is an important variable in establishing a valid kininogen-dependent aPE assay. In FCS, the concentration of kininogens is <50% of adult values; thus, FCS is neither an optimal patient serum diluent nor an appropriate aPE ELISA-blocking reagent. ELISA results that demonstrate these different outcomes are shown in Table I. Furthermore, certain lots of bovine sera contain inactive kininogens and do not support detection of kininogen-dependent aPE (McIntyre and Wagenknecht, 2000). To avoid these vagaries for kininogen-dependent aPE detection the use of adult bovine plasma in the patient serum diluents is necessary. We also recommend the parallel use of bovine serum albumin (BSA) as the ELISA well-block and the patient’s serum diluent to allow detection of plasma-protein independent aPE as the latter aPE also have been associated with pathology (Wagenknecht et al., 1999; Sokol et al., 2000).
|
The authors did not reveal raw data findings for aPI, aPG or aPE. Of these three ‘other’ aPL specificities, only aPE involves a zwitterionic phospholipid. We are surprised that aPI and aPG were detected independently from aCL and aPS. Since all aPL tested, except aPE, involved negatively charged phospholipids, one might expect them also to bind the FCS ‘co-factor’ proteins (e.g., beta2-glycoprotein I, prothrombin, etc.) presented on each of these anionic phospholipid substrates.
Lastly, the authors’ findings of aPE associated RPL are not novel. Sugi et al. (1999) previously reported an aPE relationship with recurrent miscarriage. A subsequent paper published by Gris et al. (2000), was not referenced despite their findings that aPE was the most significant risk factor associated with early RPL in a French cohort of 518 patients with unexplained repeated losses. Nonetheless, we are in agreement with the authors that aPL other than aCL, aPS and/or LAC should not go unrecognized as having an association with pregnancy failures. Furthermore, heparin and aspirin therapy may be beneficial for all aPL-positive patients, pregnancy history notwithstanding.
References
Di Simone, N., Ferrazzani, S., Castellani, R., De Carolis, S., Manscuso, S. and Caruso, A. (1997) Heparin and low dose aspirin restore placental human chorionic gonadotrophin secretion abolished by antiphospholipid antibody-containing sera. Hum. Reprod., 12, 2061–2065.
Di Simone, N., Meroni, P.L., del Papa, N., Raschi, E., Caliandro, D., De Carolis, C.S., Khamashta, M.A., Atsumi, T., Hughes, G.R., Balestrieri, G. et al. (2000) Antiphospholipid antibodies affect trophoblast gonadotrophin secretion and invasiveness by binding directly and through adhered beta2-glycoprotein I. Arthritis Rheum., 43, 140–150.[CrossRef][Web of Science][Medline]
Franklin, R.D. and Kutteh, W.H. (2002) Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique APA positive population. Hum. Reprod., 17, 2981–2985.
Gallart, T., Benito, C., Reverter, J.C., Bosch, F., Blay, M., Tassies, D., Vigorito, E., Cervera, R., Font, J., Gomis, R. et al. (2002) True anti-anionic phospholipid immunoglobulin M antibodies can exert lupus anticoagulant activity. Br. J. Rheumatol., 116, 875–886.
Gris, J.C., Quere, I., Sanmarco, M., Boutiere, B., Mercier, E., Amiral, J., Hubert, A.M., Ripart-Neveu, S., Hoffet, M., Tailland, M.L. et al. (2000) Antiphospholipid and antiprotein syndromes in non-thrombotic, non-autoimmune women with unexplained recurrent primary early foetal loss. Thromb. Haemost., 84, 228–236.[Web of Science][Medline]
Katsuragawa, H., Kanzaki, H., Inoue, T., Hirano, T., Mori. T. and Rote, N.S. (1997) Monoclonal antibody against phosphatidylserine inhibits in vitro human trophoblastic hormone production and invasion. Biol. Reprod., 56, 50–58.[Abstract]
Matsuura, E., Igarashi, Y., Fujimoto, M., Ichikawa, K. and Koike, T. (1990) Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet, 336, 177–178.[Web of Science][Medline]
Matsuura, E., Igarashi, Y., Fujimoto, M., Ichikawa, K., Suzuki, T., Sumida, T., Yasuda, T. and Koike, T. (1992) Heterogeneity of anticardiolipin antibodies defined by the anticardiolipin cofactor. J. Immunol., 148, 3885–3891[Abstract]
McIntyre, J.A. and Wagenknecht, D.R. (2000) Antiphosphatidylethanolamine antibodies (aPE): a survey. J. Autoimmun., 15, 185–193.[CrossRef][Medline]
Ozawa, N., Makino, T., Matsubayashi, H., Hosokawa, T., Someya, K-i., Nozawa, S., and Matsuura, E. (1994) 
2-GPI-dependent and independent binding of anticardiolipin antibodies in patients with recurrent spontaneous abortions. J. Clin. Lab. Anal., 8, 255–259.[Medline]
Sokol, D.K., McIntyre, J.A., Short, R., Gutt, J., Wagenknecht, D.R., Biller, J. and Garg, B. (2000) Henoch-Schönlein Purpura and stroke: antiphosphatidylethanolamine antibody (aPE) in CSF and serum. Neurology, 55, 1379–1381.
Sugi, T. and McIntyre, J.A. (1995) Autoantibodies to phosphatidyl ethanolamine (PE) recognize a kininogen-PE complex. Blood, 86, 3083–3089.
Sugi, T., Katsunuma, J., Izumi, S., McIntyre, J.A. and Makino, T. (1999) Prevalence and heterogeneity of antiphosphatidylethanolamine antibodies in patients with recurrent early pregnancy losses. Fertil. Steril., 71, 1060–1065.[CrossRef][Web of Science][Medline]
Wagenknecht, D.R., Becker, D.G., LeFor, W.M. and McIntyre, J.A. (1999) Antiphospholipid antibodies are a risk factor for early renal allograft failure. Transplantation, 68, 241–246.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||