Thrombosis in Immune Thrombocytopenia Patients with Antiphospholipid Antibodies: A Meta-Analysis

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 1^st 1980 to December 31^st 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 Unpublished studies were searched in meeting abstracts of the American Society of Hematology, the European Haematology Association, the American College of Rheumatology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Results: Searching in electronic databases retrieved 776 citations, completed by 12 additional studies from unpublished literature.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.