Autoimmune hemolytic anemia and venous thromboembolism: A systematic review and meta-analysis

doi:10.1016/j.thromres.2015.09.004

Thrombosis Research

Volume 136, Issue 5, November 2015, Pages 1013-1017

https://doi.org/10.1016/j.thromres.2015.09.004 Get rights and content

Highlights

•
Patients with AIHA have a higher risk of venous thromboembolism.
•
The pooled risk ratio is 2.63 (95% 1.37–5.05).
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Mechanism behind this association is unclear and merits further study.

Abstract

Objective

To investigate the risk of venous thromboembolism (VTE) among patients with autoimmune hemolytic anemia (AIHA).

Methods

We conducted a systematic review and meta-analysis of observational studies that reported odds ratio, relative risk, hazard ratio or standardized incidence ratio comparing the risk of VTE in patients with AIHA versus participants without AIHA. Pooled risk ratio and 95% confidence intervals were calculated using a random-effect, generic inverse variance method of DerSimonian and Laird.

Results

Out of 592 potentially relevant articles, four studies (three cohort studies and one cross-sectional study) met our inclusion criteria and were included in the data analysis. The pooled risk ratio of VTE in patients with AIHA was 2.63 (95% CI, 1.37–5.05). The statistical heterogeneity of this study was high with an I² of 97%.

Conclusions

Our study demonstrated a significantly increased risk of VTE among patients with AIHA.

Introduction

Autoimmune hemolytic anemia (AIHA) is a rare autoimmune disorder in which auto-antibodies against red blood cell (RBC) surface antigens are produced, resulting in premature peripheral destruction of RBCs [1]. The estimated incidence in adult is 1–3 per 100,000 person-years [2], [3]. AIHA is pathophysiologically divided into warm, mixed and cold-reactive subtypes, based on the optimal RBC-autoantibody reactivity temperature. AIHA due to warm antibodies is the most common subtype which accounts for approximately 75% all AIHAs in adults [4]. Warm-reactive AIHA could be found in isolation or in association which various conditions including lymphoproliferative disorders, rheumatic diseases, primary immunodeficiency, solid tumors and drugs [1], [4].

The association between venous thromboembolism (VTE) and AIHA has long been recognized. In 1967, Allgood et al. reported that pulmonary embolism (PE) was the most common cause of death in their cohort of 47 patients [5]. Subsequent studies have revealed a similar high incidence of VTE [4], [6], [7]. In fact, an increased risk of VTE in patients with non-immune hemolytic anemia, such as paroxysmal nocturnal hemoglobinuria and thalassemia, has been well-documented [8], [9]. However, the number of epidemiological studies on VTE risk patients with AIHA is still limited. Therefore, to summarize all available data, we conducted a systematic review and meta-analysis of observational studies that compared the VTE risk in patients with AIHA versus non-AIHA participants.

Section snippets

Search strategy

Two investigators (P.U. and P.T.) independently searched published studies indexed in MEDLINE and Embase from inception to June 2015 using the search terms described in supplementary data. References of selected articles were also manually searched.

Inclusion criteria

Studies were eligible for this meta-analysis if they met the following inclusion criteria: (1) Observational study (case–control, cohort or cross-sectional study) published as original study or conference abstract to evaluate the association between

Result

Our search strategy yielded 592 potentially relevant articles (107 articles from Medline and 485 articles from Embase). After exclusion of 98 duplicated articles, 494 of them underwent title and abstract review. Four hundred and sixty articles were excluded as they were not case–control, cross-sectional or cohort studies or were not conducted in patients with AIHA, leaving 34 articles for a full-length article review. Fifteen articles were excluded since they did not report the outcome of

Discussion

This study is the first meta-analysis to summarize all available data on VTE risk among patients with AIHA. We found that patients with AIHA had a 2.6-fold higher risk of VTE compared with non-AIHA participants. The risk was more pronounced in the first year after diagnosis.

The reasons as to why patients with AIHA were at an increased risk of AIHA remain unclear. The most widely accepted hypothesis is related to the alteration of RBC membrane organization due to the destruction of RBC membrane

Conclusion

Our study demonstrated a significantly increased VTE risk among patients with AIHA. Further studies are required to clarify how this risk should be addressed.

The following are the supplementary data related to this article.

. Search strategy.

. Forest plot of VTE risk during the first year after diagnosis.

. Forest plot of patients < 40 years old.

. Forest plot of patients > 40 years old.

Funding

None.

Conflict of interest statement for all authors

We do not have any financial or non-financial potential conflicts of interest.

Authors' contributions

All authors had access to the data and a role in writing the manuscript.

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Thromboembolic complications have been recognized to contribute to the morbidity and mortality in AIHA [18,19]. The incidence of these thrombotic events has been estimated between 11 and 27% [19,20] and AIHA patients have a 2-fold higher risk of venous thromboembolism (most affected sites summarized in Table 1) compared to matched non-AIHA controls [21,22]. Finally, aHUS as a hemolytic disease is caused by complement activation.
Thromboembolic events represent the most common complication of hemolytic anemias characterized by complement-mediated hemolysis such as paroxysmal nocturnal hemoglobinuria and autoimmune hemolytic anemia. Similarly, atypical hemolytic uremic syndrome is characterized by hemolysis and thrombotic abnormalities. The main player in the development of thrombosis in hemolytic diseases is suggested to be the complement system. However, the release of extracellular hemoglobin and heme by hemolysis itself can also drive procoagulant responses. Both, complement activation and hemolysis promote the activation of neutrophils resulting in the formation of neutrophil extracellular traps and induce inflammation and vascular damage which all together might (synergistically) lead to hypercoagulability. In this review we aim to summarize the current knowledge on the role of complement activation and hemolysis in the onset of thrombosis in hemolytic diseases. This review will discuss the interplay between different biological systems and neutrophil activation contributing to the pathogenesis of thrombosis. Finally, we will combine this fundamental knowledge and address the pathophysiology of hemolysis in prototypical complement-driven diseases.
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Thromboembolism is a serious complication of disorders caused by immunoglobulin G (IgG)–containing immune complexes (ICs), including heparin-induced thrombocytopenia (HIT),1 antiphospholipid syndrome (APS),2,3 and warm autoimmune hemolytic anemia (WAHA).4-6
Thromboembolism complicates disorders caused by immunoglobulin G (IgG)–containing immune complexes (ICs), but the underlying mechanisms are incompletely understood. Prior evidence indicates that induction of tissue factor (TF) on monocytes, a pivotal step in the initiation, localization, and propagation of coagulation by ICs, is mediated through Fcγ receptor IIa (FcγRIIa); however, the involvement of other receptors has not been investigated in detail. The neonatal Fc receptor (FcRn) that mediates IgG and albumin recycling also participates in cellular responses to IgG-containing ICs. Here we asked whether FcRn is also involved in the induction of TF-dependent factor Xa (FXa) activity by IgG-containing ICs by THP-1 monocytic cells and human monocytes. Induction of FXa activity by ICs containing IgG antibodies to platelet factor 4 (PF4) involved in heparin-induced thrombocytopenia (HIT), β-2-glycoprotein-1 implicated in antiphospholipid syndrome, or red blood cells coated with anti-(α)-Rh(D) antibodies that mediate hemolysis in vivo was inhibited by a humanized monoclonal antibody (mAb) that blocks IgG binding to human FcRn. IgG-containing ICs that bind to FcγR and FcRn induced FXa activity, whereas IgG-containing ICs with an Fc engineered to be unable to engage FcRn did not. Infusion of an α-FcRn mAb prevented fibrin deposition after microvascular injury in a murine model of HIT in which human FcγRIIa was expressed as a transgene. These data implicate FcRn in TF-dependent FXa activity induced by soluble and cell-associated IgG-containing ICs. Antibodies to FcRn, now in clinical trials in warm autoimmune hemolytic anemia to lower IgG antibodies and IgG containing ICs may also reduce the risk of venous thromboembolism.
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Full Length ArticleAutoimmune hemolytic anemia and venous thromboembolism: A systematic review and meta-analysis