Antiphosphatidylserine/prothrombin (aPS/PT) antibodies are associated with Raynaud phenomenon and migraine in primary thrombotic antiphospholipid syndrome

Abstract

Objectives

Antibodies to phosphatidylserine/prothrombin complex (aPS/PT) detectable in sera of some patients with antiphospholipid syndrome (APS) have been shown to correlate with thrombosis. However, associations of aPS/PT antibodies with APS related disorders remain unclear.

Aim

To evaluate whether there are any associations between aPS/PT antibodies and Raynaud phenomenon, migraine and/or valvular lesions in primary thrombotic APS (PAPS).

Methods

We enrolled 67 consecutive patients (56 women) with thrombotic PAPS (VTE in 80.6%), aged 46.2 ± 13.5 years. The exclusion criteria were: acute coronary syndromes or stroke within preceding 6 months, cancer, severe comorbidities and pregnancy. The IgG and IgM aPS/PT antibodies were determined by ELISA with the cut-off of 30 units. We recorded Raynaud phenomenon, migraine and valvular lesions.

Results

Positive IgM or/and IgG aPS/PT antibodies were observed in 29 patients (43.3%), with a higher prevalence of IgM antibodies (n = 27, 40.3%) compared with IgG isotype (n = 12, 17.9%, p = 0.014). aPS/PT antibodies were observed most commonly in patients with triple aPL (n = 12, 85.7%) compared with those with double (n = 5, 35.7%) or single aPL antibodies (n = 12, 30.8%, p = 0.03), with no association with demographics, the ANA titre, the type of thrombotic events or medications. Raynaud phenomenon, migraine and valvular lesions were observed in 15% (n = 10), 30% (n = 20) and 18% (n = 12) of the patients, respectively. Raynaud phenomenon and migraine, but not valvular lesions, were markedly more frequent in PAPS patients presenting with positive aPS/PT antibodies (n = 10, 34.5% vs. n = 0, 0%; p = 0.0001).

Conclusions

In PAPS patients aPS/PT antibodies are related to the occurrence of both Raynaud phenomenon and migraine.

Keywords

Primary antiphospholipid syndrome (PAPS)thrombosis Raynaud phenomenon antiphosphatidylserine/prothrombin (aPS/PT) antibodies antiphospholipid (aPL) antibodies

Get full access to this article

View all access options for this article.

References

Hughes

GRV

. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341–344.

Miyakis

Lockshin

Atsumi

et al.

International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306.

Arvieux

Darnige

Caron

et al.

Development of an ELISA for autoantibodies to prothrombin showing their prevalence in patients with lupus anticoagulants. Thromb Haemost 1995; 74: 120–1125.

Atsumi

Ieko

Bertolaccini

et al.

Association of autoantibodies against the phosphatidylserine-prothrombin complex with manifestations of the antiphospholipid syndrome and with the presence of lupus anticoagulant. Arthritis Rheum 2000; 43: 1982–1993.

Galli

Barbui

. Antiprothrombin antibodies: detection and clinical significance in the antiphospholipid syndrome. Blood 1999; 93: 2149–2157.

Vlagea

Gil

Cuesta

et al.

Antiphosphatidylserine/prothrombin antibodies (aPS/PT) as potential markers of antiphospholipid syndrome. Clin Appl Thromb-Hemost 2013; 19: 289–296.

Hoxha

Mattia

Tonello

et al.

Antiphosphatidylserine/prothrombin antibodies as biomarkers to identify severe primary antiphospholipid syndrome. Clin Chem Lab Med 2016; 55: 890–898.

Bertolaccini

Atsumi

Koike

et al.

Antiprothrombin antibodies detected in two different assay systems. Prevalence and clinical significance in systemic lupus erythematosus. Thromb Haemost 2005; 93: 289–297.

Bertolaccini

Sciascia

Murru

et al.

Prevalence of antibodies to prothrombin in solid phase (aPT) and to phosphatidylserine-prothrombin complex (aPS/PT) in patients with and without lupus anticoagulant. Thromb Haemost 2013; 109: 207–213.

10.

Heikal

Jaskowski

Malmberg

et al.

Laboratory evaluation of anti-phospholipid syndrome: a preliminary prospective study of phosphatidylserine/prothrombin antibodies in an at-risk patient cohort. Clin Exp Immunol 2015; 180: 218–226.

11.

Nojima

Iwatani

Suehisa

et al.

The presence of anti-phosphatidylserine/prothrombin antibodies as risk factor for both arterial and venous thrombosis in patients with systemic lupus erythematosus. Haematologica 2006; 91: 699–702.

12.

Hoxha

Ruffatti

Tonello

et al.

Antiphosphatidylserine/prothrombin antibodies in primary antiphospholipid syndrome. Lupus 2012; 21: 787–789.

13.

Francès

Niang

Laffitte

et al.

Dermatologic Manifestations of the Antiphospholipid Syndrome: Two Hundred Consecutive Cases. Arthritis Rheum 2005; 52: 1785–1793.

14.

Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 2013; 33: 629–808.

15.

Pengo

Tripodi

Reber

et al.

Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 2009; 7: 1737–1740.

16.

Amengual

Forastiero

Sugiura-Ogasawara

et al.

Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study. Lupus 2017; 26: 266–276.

17.

Agmon-Levin

Damoiseaux

Kallenberg

et al.

International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann Rheum Dis 2014; 73: 17–23.

18.

Knapik-Kordecka

Wysokinski

. Clinical spectrum of Raynaud's phenomenon in patients referred to vascular clinic. Cardiovasc Surg 2000; 8: 457–462.

19.

Vayssairat

Abuaf

Baudot

et al.

Abnormal IgG cardiolipin antibody titers in patients with Raynaud's phenomenon and/or related disorders: prevalence and clinical significance. J Am Acad Dermatol 1998; 38: 555–558.

20.

Bongard

Bounameaux

Miescher

et al.

Association of anticardiolipin antibodies and abnormal nailfold capillaroscopy in patients with systemic lupus erythematosus. Lupus 1995; 4: 142–144.

21.

Caccavo

Del Porto

Garzia

et al.

Raynaud's phenomenon and antiphospholipid antibodies in systemic lupus erythematosus: is there an association?

Ann Rheum Dis 2003; 62: 1003–1005.

22.

Rodriguez

Gonzalez-Pares

Rivera

. Clinical manifestations and vascular events in patients with lupus erythematosus anticardiolipin antibodies and Raynaud's phenomenon. P R Health Sci J 2006; 25: 307–313.

23.

Griffiths

Papadaki

Neild

. The renal pathology of primary antiphospholipid syndrome: a distinctive form of endothelial injury. QJ Med 2000; 93: 457–467.

24.

Neville

Rauch

Kassis

et al.

Antiphospholipid antibodies predict imminent vascular events independently from other risk factors in a prospective cohort. Thromb Haemost 2009; 101: 100–7.

25.

Pregnolato

Chighizola

Encabo

et al.

Anti-phosphatidylserine/prothrombin antibodies: an additional diagnostic marker for APS?

Immunol Res 2013; 56: 432–438.

26.

Garner

Kumari

Lanyon

et al.

Prevalence, risk factors and associations of primary Raynaud's phenomenon: systematic review and meta-analysis of observational studies. BMJ Open 2015; 5: e006389.

27.

Herrick

. The pathogenesis, diagnosis and treatment of Raynaud phenomenon. Nat Rev Rheumatol 2012; 8: 469–479.

28.

Oku

Amengual

Zigon

et al.

Essential role of the p38 mitogen-activated protein kinase pathway in tissue factor gene expression mediated by the phosphatidylserine-dependent antiprothrombin antibody. Rheumatology (Oxford) 2013; 52: 1775–1784.

29.

Schreiber

Feagan

D'Haens

et al.

Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2006; 4: 325–334.

30.

Meroni

Chighizola

Rovelli

et al.

Antiphospholipid syndrome in 2014: more clinical manifestations, novel pathogenic players and emerging biomarkers. Arthritis Res Ther 2014; 16: 209.

31.

Annese

Tomietto

Venturini

et al.

Migraine in SLE: role of antiphospholipid antibodies and Raynaud's phenomenon. Reumatismo 2006; 58: 50–58.

32.

Atsumi

Koike

. Antiprothrombin Antibody: Why Do We Need More Assays? Lupus 2010; 19: 436–439.