Is APS Hereditary?

An intriguing case from Heather DeVries, Indiana University Health.

Hi George, I have an interesting (cold) case study for you. We recently tested a 44 yo female for lupus antibodies and she had textbook results–nothing equivocal about them. Her history includes a late-term pregnancy loss 12 years ago, and a recent diagnosis of lupus, so it seems that she could now be considered to have antiphospholipid antibody syndrome (APS). This is where the family history comes in.

Her maternal grandmother had a stroke while pregnant with her third child in her 30s, and another in her 70s that was ultimately fatal. There was never an explanation for the stroke during pregnancy.  Is it possible that she had undetected antiphospholipid antibodies? I have never seen anything about them being hereditary, and would love to hear any thoughts/opinions from the coag community. Thanks, Heather

From George, Hi, Heather, and thank you for this case. I started to belittle the idea that APS could be hereditary, or could have a familial distribution, however a quick PubMed search turned up this, the most recent of several articles that connect APS with HLA system antigens:

Sebastiani GD, Iuliano A, Cantarini L, Galeazzi M. Genetic aspects of the antiphospholipid syndrome: An update.. Autoimmun Rev. 2016;15:433–9.
Abstract
Studies on the immunogenetic predisposition to antiphospholipid syndrome (APS) and on other non-genetic and epigenetic factors are summarised and discussed. Family studies suggest a genetic predisposition to APS. It appears that this genetic predisposition is in part accounted for by the HLA system, the most consistent associations being those with DR4 and DRw53. Furthermore, it appears that lupus anticoagulant (LA) and anticardiolipin (aCL) antibodies are both associated with the same HLA antigens. Population studies suggest that HLA genes have a role in conferring susceptibility to develop primary APS, with some differences in different ethnic groups. Other genes, outside the MHC, give their contribution to the development of this autoimmune syndrome, such as IRF5, STAT4 and those related to inherited thrombophilia–factor V Leiden and G20210A prothrombin polymorphisms. Finally, post-transcriptional modifications of anti-beta2GPI antibodies could be implicated too.