Thrombosis in Immune Thrombocytopenia Patients with Antiphospholipid Antibodies: A Meta-Analysis
Authors: Moulis Guillaume , Audermard-Verger Alexandra , Arnaud Laurent , Luxembourger Cécile , Montastruc François , Gaman Amelia Maria , Svenungsson Elisabet , Ruggeri Marco , Mahévas Matthieu , Gerfaud-Valentin Mathieu , Brainsky Andres , Michel Marc , Godeau Bertrand , Laurent Guy , Mapeyre-mestre Maryse , Sailler Laurent 
Published: October 2019

Abstract
Background: Thrombosis during immune thrombocytopenia (ITP) management is a critical issue. Among suspected risk factors for thrombosis in ITP patients, the role of antiphospholipid antibodies (aPL) is controversial. We performed a systematic review and a meta-analysis to investigate risk of thrombosis with lupus anticoagulant (LA), anticardiolipin (aCL) and anti-β2GP1 antibodies in primary ITP.
Methods: Literature search was computed on Medline, Cochrane and ISI Web of Sciences by two independent investigators from January 1st 1980 to December 31st 2014. Unpublished studies were searched in meeting abstracts of the American Society of Hematology, the European Haematology Association, the American College of Rheumatology and the European League Against Rheumatism. Inclusion criteria were observational studies including primary ITP patients where presence of aPL was documented (LA, aCL or anti-β2GP1 antibodies). We assessed the occurrence of thrombotic events in these studies. Two investigators performed data extraction. All authors were contacted in order to confirm or provide complementary data if needed. Study quality was assessed using the NewCastle-Ottawa (NOS) scale. The main analysis assessed the risk of all thromboses (arterial or venous) associated with the presence of LA, aCL or anti-β2GP1 antibodies. Sensitivity analyses were performed, restricted to the best quality studies. We also also stratified the risk of arterial and venous thrombosis separately. Random effect (Der Simonian & Laird) models were used. Heterogeneity was assessed using the I2 index. Odds ratio (OR) and their 95% confidence intervals (95%CI) were computed. Publication bias was searched using Egger's test and funnel plot.
Results: Searching in electronic databases retrieved 776 citations, completed by 12 additional studies from unpublished literature. Out of them, 44 studies were identified for a full-length text review. Eventually, 10 cohort studies totalizing 1010 patients were selected (9 with LA, 6 with aCL, 2 with anti-β2GP1 antibody dosages). Five studies were prospective and 5 retrospective. The median NOS score was 6 (range: 4-8). The pooled OR for the risk of all thromboses associated with LA positivity was 6.11, 95%CI [3.40-10.99] (I2 =0%, Egger's test: p=0.37). It was 2.13, 95%CI [1.11-4.12] with aCL (I2 =0%, Egger's test: p=0.14). Sensitivity analyses restricted to studies with quality score ≥6 led to similar results. The OR for arterial thrombosis was 5.52, 95%CI [2.40-12.70] with LA and 2.12, 95%CI [0.84-5.33] with aCL. The OR for venous thrombosis was 5.13, 95%CI [2.31-11.40] with LA and 2.00, 95%CI [0.83-4.81] with aCL. Only two studies assessed the risk of thrombosis associated with anti-β2GP1 antibody positivity, with high heterogeneity (I2 =81%). Consequently, no pooled OR was computed.
Conclusions: This meta-analysis demonstrates that aPL positivity in ITP patients is a risk factor for thrombosis. The risk was three times higher with LA than with aCL. It was similar for arterial and venous thromboses. For practicing clinicians, our results imply that systematic aPL determinations should be performed in ITP, since aPL positivity and associated thrombosis risk should influence the choice of treatment.

Disclosures
Michel: Roche: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Godeau:Roche: Research Funding; Amgen: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.