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You Make the Call: How would you proceed to diagnose a woman with extremely high ANA levels and repeated miscarriages?

July 25, 2022

August 2022

Fernanda Andrade Orsi, MD, PhD Department of Pathology University of Campinas São Paulo, Brazil

Fernanda Andrade Orsi, MD, PhD
Department of Pathology
University of Campinas
São Paulo, Brazil




I have a 31-year-old female patient with recurrent pregnancy loss. She has had three miscarriages; the first two occurred in the first trimester and the third happened in the second trimester. She does not have a history of deep vein thrombosis or pulmonary embolism. To identify a cause for the recurrent pregnancy loss, a work-up for autoimmune disorders and antiphospholipid syndrome (APS) was completed. Her antinuclear antibody (ANA) titer was 1:1280. Her IgG, IgM, and IgA anticardiolipin antibody (aCL) titers were 9, 27 (previously 17), and 9 units, respectively. She was also found to have mild proteinuria (248 mg/24 hr). She was evaluated by a rheumatologist who did not identify any rheumatologic disorders or syndromes.

Since the aCL IgM is weak, my impression is that this patient does not have APS. However, despite the negative rheumatologic work-up, I am bothered by the recurrent pregnancy losses and the elevated ANA titer. I think she has something, and my question is, “What can I do as a hematologist?” Do you recommend anticoagulation or low-dose aspirin at 81 mg daily? Are there any other tests you recommend? I ordered a standard hypercoagulability work-up that was otherwise negative. I asked the patient to get a second opinion from another rheumatologist and to see a high-risk obstetrician, but I feel something is missing. Maybe we should be doing something different; otherwise she will keep getting the same negative outcomes.


This is an intriguing case of a young woman with recurrent pregnancy losses for which the most important differential diagnosis is APS, an autoimmune disorder characterized by thrombotic events or obstetric morbidities coinciding with the persistent presence of antiphospholipid antibodies (aPL). Patients with aPL are two to four times more likely to develop adverse pregnancy outcomes, such as fetal loss, preeclampsia, and intrauterine growth restriction than non-aPL carriers.1,2

In patients with thrombosis or adverse pregnancy outcomes, the presence of aPL and, therefore, the diagnosis of APS are confirmed according to the following laboratory criteria: 

  • positive lupus anticoagulant (LAC)
  • IgG or IgM aCL at medium or high titer (>40 GPL/MPL or >99th percentile)
  • IgG or IgM anti-beta-2 glycoprotein 1 (aβ2GP1) at medium or high titer (>99th percentile) 

To confirm an APS diagnosis, at least one of these laboratory criteria must be present on two or more occasions at a minimum of 12 weeks apart.3 Particularly, LAC positivity seems to be more prevalent than aCL in women with a history of recurrent miscarriages.4 

The patient was tested only for IgG and IgM aCL, which were negative. There is no mention of LAC and aβ2GP1 results. I believe it is not possible to rule out the diagnosis of obstetric APS in this case only based on aCL results, and further laboratory work-up is necessary. Therefore, I would suggest testing for the presence of LAC and aβ2GP1 before any diagnosis or treatment is considered.


  1. Lynch A, Marlar R, Murphy J, et al. Antiphospholipid antibodies in predicting adverse pregnancy outcome: a prospective study. Ann Intern Med. 1994;120(6):470-5.
  2. Abou-Nassar K, Carrier M, Ramsay T, Rodger MA. The association between antiphospholipid antibodies and placenta mediated complications: a systematic review and meta-analysis. Thromb Res. 2011;128(1):77-85.
  3. 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(2):295-306.
  4. Buyon JP, Kim MY, Salmon JE. Predictors of pregnancy outcomes in patients with lupus. Ann Intern Med. 2016;164(2):131.


A 59-year-old patient was referred to me after a circulating tumor DNA screening test indicated he likely had a lymphoproliferative cancer. Extensive work-up revealed enlarged lymph nodes (2-3 cm in size) in the retroperitoneum and iliac region. A PET scan confirmed uptake of radiotracer by these nodes, as well as a focal splenic lesion. All other work-up (labs and bone marrow biopsy) have come back negative, but the lymph node biopsy showed nodular lymphocyte-predominant Hodgkin lymphoma. What would you advise?

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Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.


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