Open Access

Acquired factor XII deficiency in a woman with recurrent pregnancy loss: working on a differential diagnosis in a single case

  • Maristella D'Uva1,
  • Ida Strina1,
  • Antonio Mollo1,
  • Antonio Ranieri1,
  • Giuseppe De Placido1 and
  • Pierpaolo Di Micco1, 2Email author
Journal of Translational Medicine20053:43

https://doi.org/10.1186/1479-5876-3-43

Received: 05 October 2005

Accepted: 02 December 2005

Published: 02 December 2005

Abstract

Background

Antiphospholipid syndrome (APS) has been often associated to RPL since 1980 and some reports in the Literature rarely described antibodies to factor XII in patients with APS.

Case history

We report the case history of 34-year-old caucasian women with recurrent fetal loss and persistent prolonged activated partial thromboplastin time. Haemostatic tests revealed persistent light decrease of clotting factor XII with normal values of IgG and IgM anticardiolipin antibodies and transient positivity for lupus anticoagulant (LA). Few reports in the Literature described antibodies to factor XII in patient with antiphospholipid syndrome (APS) and transient LA. So, once other causes of RPL were excluded, the patient was diagnosed an unusual form of APS associated to antibodies to factor XII, reduced factor XII plasma levels, transient LA and prolonged activated partial thromboplastin time.

Discussion

We suggest to consider also antibodies directed to clotting factors (e.g. factor XII in our case) as second step of thrombophilia screening in RPL, in particular if a persistent prolonged aPTT is present without an apparent cause.

Background

Recurrent pregnancy loss (RPL) is one of the most common cause of sterility. An our recent study underlined the relevant role of d-dimer, as marker of hypercoagulable state, to identify thrombophilia in women affected by primary or secondary sterility [1]

In 1999 a study written by Brenner et al. identified thrombophilia as principal cause of more than 40% of women affected by RPL [2]. Further studies underlined a pathogenetic role of inherited thrombophilia in women affected by RPL. Sanson et al., in fact, reported an increased frequency of antithrombin III, protein C and protein S deficiency in women with RPL [3], while Grandone et al. found an increased incidence of factor V Leiden in women with unexplained RPL [4]. Also prothrombin A20210G gene polymorphism has been reported as possible cause of RPL in several studies [2, 5, 6].

Yet, also acquired thrombophilia has been associated to RPL. A study by Dossenbach et al., in fact, revealed that elevated maternal plasma levels of clotting factor VIII tend to be associated to an increased risk of RPL [7]. Moreover, several studies in the Literature are available for the association of RPL and primary or secondary antiphospholipid syndrome [8, 9]. On this topic also a rare condition as acquired deficiency of clotting factor XII has been described. Braulke et al. identified for the first time a factor XII deficiency in RPL [10], but subsequently Jones et al. reported acquired factor XII deficiency in a subpopulation of women with antiphospholipid antibodies and RPL [1113]. We here report a really interesting case report of woman affected by unexplained RPL, prolonged activated partial thrombplastin time and mild/moderate reduction of clotting factor XII.

Case presentation

A 34-year-old Caucasian non smoking woman was referred to our Sterility Center. Her personal anamnesis revealed three early pregnancy loss within 8 and 12 week of gestation and one extrauterine pregnancy. The patient did not revealed previous thromboembolic disease (arterial or venous) nor haemorragic disorders; moreover patient was not ongoing any type of pharmacological treatment. A thorough familial anamnesis did not show a trend toward thromboembolic and/or haemorragic disease.

To understand pathophysiology of her RPL the patient performed several laboratory and instrumental tests.

A normal ovarian function and ovulation were detected by normal values of Follicle-stimulating Hormone, Luteinising Hormone, oestradiol and progesterone and by ovarian ultrasound scan (data not shown). Uterine and salpinxes malformation was excluded by hysterosalpingography and hysteroscopy (data not shown). Endocrinological diseases such as diabetes and dysthyroidism were evaluated and excluded by normal values of glycaemia, thriiodothyronine (i.e. FT3), thyroxine (i.e. FT4) and Thyroid-stimulating Hormone (data not shown). Inflammatory chronic diseases were excluded by normal values of erythro-sedimentation rate and acute phase C reactive protein and immunopathological chronic disease, such as erytematosus systemic lupus, by normal level of antinuclear antibodies (ANA), anitmithocondrial antibodies (AMA) and smooth muscle antibodies (SMA) too (data not shown); moreover patient did not suffer of chronic joint paint or fever or other related symptoms.

Yet, routine haemostatic tests showed normal value of prothrombin time, measured as International Normalised Ratio (PT INR, 1.15) and a prolonged activated thromboplastin time, measured as ratio (aPTT, 1.45) (table 1). To confirm this laboratory alteration, after 15 days a second step of haemostatic parameters were tested and confirmed normal value of PT INR and prolonged aPTT (1.46, table 1 and 2), associated to normal levels of anticardiolipin antibodies (tested by an ELISA method; IgM 1.7 U/MPL and IgG 3.9 U/GPL) (table 1 and 2), fibrinogen and clotting factors V, VIII, IX, X, XI (table1), while a reduced plasmatic level of clotting factor XII was detected (65%, table 1 and 2). So, we tested for aPTT and factor XII first degree relatives (i.e. one sister and parents) but did not find alterations (data not shown). Yet, lupus anticoagulant and antibodies to β-2-glycoprotein I were absent (table 1 and 2). Furthermore, because RPL was associated to reduced clotting inhibitors also protein C, protein S and antithrombin III were analysed and resulted in normal range (table 1) such as inherited thrombophilia associated to Factor V Leiden and prothrombin A20210G gene polymorphisms (table 1). Moreover, to confirm factor XII deficiency, after one month the patient was evaluated again and results showed again prolonged aPTT (1.48), reduced factor XII (55%). So, we tested aPTT adding to the plasma patient's a normal plasma sample with a ratio of plasma patient's to pool plasma 1/1 v/v; results revealed a partial correction of aPTT (1.30) suggesting a possible presence of an acquired clotting inhibitor and/or antiphospholipid antibodies. A new evaluation of common antiphospholipid antibodies began with normal levels of anticardiolipin antibodies (tested again with an ELISA method; IgM 1.5 and IgG 3.8) and absence of antibodies to β-2-Glycoprotein I, but a positivity for lupus anticoagulant was detected (table 2). Lupus anticoagulant was assayed according to recommendations of the International Society of Thrombosis and Haemostasis. Furthermore, at this time we tested again ANA that resulted again negative. Finally, because a transient positivity of lupus anticoagulant has been associated with factor XII deficiency in patients with antiphospholipid syndrome in rare cases [14, 15], after one month the patient was evaluated one more time and in this time also antibodies to clotting factor XII were evaluated by an ELISA method. Results showed prolonged aPTT (1.44), reduced factor XII plasma levels (43%), normal range of anticardiolipin antibodies (IgM and IgG), absence of antibodies to β-2-Glycoprotein I, negativity for lupus anticoagulant, while antibodies to factor XII have been detected (table 2). So, according to our data and data available in the Literature the patient was diagnosed an unusual form of primary antiphospholipid syndrome and an antithrombotic treatment was suggested.
Table 1

Screening for disorder of haemostasis in the patient with RPL.

Parameters (unit of measurement)

Results

Normal range

Prothrombin time (INR)

1.15

0.8–1.2

Activated partial thromboplastin time (ratio)

1.45

0.8–1.2

Fibrinogen (mg/dL)

275

220–420

Protein C (%)

93

60–125

Protein S (%)

92

60–125

Antithrombin III (%)

104

80–120

Anticardiolipin Ab IgM (U/GPL)

1.7

< 2.0

Anticardiolipin Ab IgG (U/MPL)

3.9

< 7.0

β-2-GP I Ab

Absent

Absent

Lupus anticoagulant

Absent

Absent

Factor XII (%)

65

80–120

Factor XI (%)

113

80–120

Factor X (%)

112

80–120

Factor IX (%)

99

80–120

Factor VIII (%)

88

65–155

Factor V (%)

110

80–120

MTHFRC677T gene polymorphism

Wild type

Wild type

PTHRA20210 gene polymorphism

Wild Type

Wild type

FVL gene polymorphism

Wild Type

Wild type

INR: international normalised ratio

MTHFRC677T: methylene-tetra-hydrp-folate reductase C677T gene polymorphism

PTHRA20210G: prothrombin A20210G gene polymorphism

FVL: factor V Leiden gene polymorphism

β-2-GP I Ab: Antibodies to β-2-glycoprotein I

Table 2

Monitor of the alteration of haemostasis in the patient with RPL.

Parameters (Unit of measurement)

First screening

Second screening

Third screening

Fourth screening

Normal value

aPTT (ratio)

1.45

1.36

1.28

1.44

0.8–1.2

Factor XII (%)

65

50

55

43

80–120

Anticardiolipin Ab IgM (U/MPL)

1.7

1.3

1.5

1.5

< 2.0

Anticardiolipin Ab IgG (U/GPL)

3.9

5.4

3.8

2.5

< 7.0

β-2-GP I Ab

Absent

Absent

Absent

Absent

Absent

Lupus anticoagulant

Absent

Absent

Present

Absent

Absent

Anti-factor XII Ab

Not tested

Not tested

Not tested

Present

Absent

Antinuclear antibodies (ANA)

Absent

Not tested

Not tested

Absent

Not tested

aPTT: activated partial thromboplastin time

ab: antibodies

β-2-GP I Ab: Antibodies to β-2-glycoprotein I

Discussion

Inherited factor XII deficiency seems to be not associated to bleeding tendency if referred to major surgery [16]. However, some individual with reduction of factor XII seems to have a trend toward thrombosis [16], but pathophysiological mechanisms underlying should be better understood. Therefore, deficiency of clotting factor XII has been reported as also thrombotic risk factor and Halbmayer et al. suggested to consider factor XII deficiency in patients with recurrent thromboembolism [17]. One of the possible mechanisms could be associated to the presence of acquired clotting inhibitors eventually associated to the presence of an antiphospholipid syndrome [18]. Acquired clotting inhibitors, in fact, have been identified in several disease and frequently are associated to a thrombophilic trend [19].

Furthermore, from a clinical point of view, alteration of haemostasis with a trend toward thrombophilia has been frequently associated to RPL [2, 8]. According to a multivariate analysis on the etiology of thrombophilia by Yamada et al., clotting factor XII deficiency has been found in 4.2% of women affected by RPL [20]. Another interesting study by Iinuma et al. underlined clotting factor XII activity and not its 46C/T gene polymorphism as cause of RPL in a selected population [21]. However, factor XII deficiency may be due to inherited deficiency or acquired deficiency during an acquired disease such as antiphospholipid syndrome. In this last condition, in fact, we may find an acquired factor XII deficiency because the presence of antibodies to factor XII; moreover antibodies to factor XII may be present during antiphospholipid syndrome alone or together to lupus anticoagulant [11]: antibodies to factor XII have been described, in fact, also in patients with antiphospholipid syndrome and transient lupus anticoagulant [14, 15]. Moreover, Jones et al. described that antibodies to factor XII can be present in women with RPL and antiphospholipid syndrome more than anticardiolipin antibodies and antibodies to β-2-glycoprotein I [11]. So, according to these data, antibodies to factor XII may be implicated in the pathophysiology of the hypercoagulable state in women with antiphospholipid syndrome showing RPL and their incidence in this clinical setting could be underestimated according to the data available from the Literature [18]. This hypothesis is really intriguing also in the case we described.

The reported patient affected by RPL, in fact, did not show an apparent cause of RPL other than reduction of clotting factor XII. Also laboratory tests, concerning thrombophilia, did not show common alteration of haemostasis associated to RPL such as factor V Leiden gene polymorphism or reduction of clotting inhibitors (i.e. protein C, protein S, antithrombin III). Yet, the clinical presentation and the presence of persistent prolonged aPTT suggested periodical tests concerning possible clotting factors deficiency and/or the presence of antiphospholipid syndrome. Results of this screening confirmed us the partial and acquired factor XII deficiency, due to the presence of antibodies to factor XII, in presence of transient lupus anticoagulant.

So, in conclusion we suggest to search in such cases also antibodies directed to clotting factors (e.g. factor XII in our case) as second step of thrombophilia screening in RPL, in particular if a persistent prolonged aPTT is present (figure 1) without an apparent cause.
Figure 1

text

Declarations

Acknowledgements

Authors thank dr. Paola Ferrazzi, Centro Tormbosi, Istituto Clinico Humanitas, Rozzano, Milan, Italy, for her helpful suggestions in writing the case; further thanks are due to Prof. Biagio Di Micco, Biochimica Clinica, Università del Sannio, Benevento, Italy for his help to perform haemostatic assays.

Authors’ Affiliations

(1)
Dipartimento Universitario di Scienze Ostetriche Ginecologiche e Medicina della Riproduzione, Area Funzionale di Medicina della Riproduzione ed Endoscopia Ginecologica, Università degli Studi di Napoli Federico II
(2)
Thrombosis Center, Istituto Clinico Humanitas "IRCCS"

References

  1. Di Micco P, D'Uva M, Strina I, Mollo A, Amato V, Niglio A, De Placido G: The role of d-dimer as first marker of thrombophilia in women affected by sterility: implications in pathophysiology and diagnosis of thrombophilia-induced sterility. J Transl Med. 2004, 2: 38-10.1186/1479-5876-2-38.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N: Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost. 1999, 82: 6-9.PubMedGoogle Scholar
  3. Sanson BJ, Fierich PW, Simioni P, Zanardi S, Hilsman MV, Girolami A, ten Cate JW, Prins MH: The risk of abortion and stillbirth in antithrombin-, protein C, and protein S deficient women. Thromb Haemost. 1996, 75: 387-388.PubMedGoogle Scholar
  4. Grandone E, Margaglione M, Colaizzo D, d'Addedda M, Cappucci G, Vecchione G: Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost. 1997, 77: 822-824.PubMedGoogle Scholar
  5. Martinelli I, Taioli E, Cetin I, Marinoni A, Gerosa S, Villa MV, Bozzo M, Mannucci PM: Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med. 2000, 343: 1015-1018. 10.1056/NEJM200010053431405.View ArticlePubMedGoogle Scholar
  6. Brenner B: Inherited thrombophilia and pregnancy loss. Thromb Haemost. 1994, 82: 634-640.Google Scholar
  7. Dossenbach-Glaninger A, von Trotsenburg M, Krugluger W, Dossenbach MR, Oberkanins C, Huber J, Hompeier P: Elevated coagulation factor VIII and the risk for maternal early pregnancy loss. Thromb Haemost. 2004, 91: 694-699.PubMedGoogle Scholar
  8. Asherson RA, Cervera R: "Primary", "secondary" and other variants of antiphospholipid syndrome. Lupus. 1994, 3: 293-298.View ArticlePubMedGoogle Scholar
  9. Noble LS, Kutteh WH, Lashey N, Franklin RD, Herrada J: Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low molecular weight heparin versus unfractioned heparin. Fertil Steril. 2005, 83: 684-690. 10.1016/j.fertnstert.2004.11.002.View ArticlePubMedGoogle Scholar
  10. Braulke I, Priggmayer M, Melloh P, Hinney B, Kostering H, Gunther H: Factor XII (Hageman) deficiency in women with abitual abortion: new subpopulation of recurrent aborters?. Fertil Steril. 1993, 53: 98-101.Google Scholar
  11. Jones DW, Mackie IJ, Gallimore MJ, Winter M: Antibodies to factor XII and recurrent fetal loss in patients with the anti-antiphospholid syndrome. Br J Haematol. 2001, 113: 550-552. 10.1046/j.1365-2141.2001.02776.x.View ArticlePubMedGoogle Scholar
  12. Jones DW, Gallimore MJ, Winter M: Recurrent abortion-antibodies to factor XII or decrease in factor XII levels?. Fertil Steril. 2001, 76: 1288-1289. 10.1016/S0015-0282(01)02917-X.View ArticlePubMedGoogle Scholar
  13. Jones DW, Gallimore MJ, Winter M: Antibodies to factor XII: a possible predictive marker for recurrent fetal loss. Immunobiology. 2003, 207: 43-46. 10.1078/0171-2985-00207.View ArticlePubMedGoogle Scholar
  14. Jones DW, Gallimore MJ, Harris SL, Winter M: Antibodies to factor XII associated to lupus anticoagulant. Thromb Haemost. 1999, 81: 387-390.PubMedGoogle Scholar
  15. Jaeger U, Kapiotis S, Pabinger I, Puchhammer E, Kyrle PA, Lechner K: Transient lupus anticoagulant associated with hypoprothrombinaemia and factor XII deficiency following adenovirus infection. Ann Hematol. 1993, 67: 95-99. 10.1007/BF01788133.View ArticlePubMedGoogle Scholar
  16. Hathaway WE, Goodnight HS: Contact factor deficiencies. Disorders of hemostasis and thrombosis. A clinical guide. Edited by: Hathaway WE, Goodnight HS Jr. 1993, New York: McGraw-Hill, 147-154.Google Scholar
  17. Halbmayer WM, Mannhalter C, Feichtinger C, Rubi K, Fisher M: The prevalence of factor XII deficiency in 103 orally anticoagulated outpatients suffering from recurrent venous and/or arterial thromboembolism. Thromb Haemost. 1992, 68: 285-290.PubMedGoogle Scholar
  18. Jones DW, Gallimore MJ, MacKie IJ, Harris SL, Winter M: Reduced factor XII levels in patients with antiphospholipid syndrome are associated with antibodies to factor XII. Br J Haematol. 2000, 110: 721-726. 10.1046/j.1365-2141.2000.02251.x.View ArticlePubMedGoogle Scholar
  19. Chalkiadakis G, Kyriakou D, Oekonomaki D, Tsiaoussis J, Alexandrakis M, Vasilakis S, Kouroumalis E: Acquired inhibitors to the coagulation factor XII associated with liver disease. Am J Gatroenterol. 1999, 94: 2551-2553. 10.1111/j.1572-0241.1999.01317.x.View ArticleGoogle Scholar
  20. Yamada H, Kato EH, Kobashi G, Ebina Y, Shimada S, Morikawa M, Yamada T, Sakuragi N, Fujimoto S: Recurrent pregnancy loss: etiology of thrombophilia. Semin Thromb Haemost. 2001, 27: 121-129. 10.1055/s-2001-14070.View ArticleGoogle Scholar
  21. Iinuma Y, Sugiura-Ogasawara M, Makino A, Ozaki Y, Suzumori N, Suzumori K: Coagulation factor XII activity, but not an associated genetic polymorphism (46C/T), is linked to recurrent miscarriage. Fertil Steril. 2002, 77: 353-356. 10.1016/S0015-0282(01)02989-2.View ArticlePubMedGoogle Scholar

Copyright

© D'Uva et al; licensee BioMed Central Ltd. 2005

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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