Application of the thrombin generation assay in patients with antiphospholipid syndrome: A systematic review of the literature

Abstract

Background: The antiphospholipid syndrome (APS) is classified by the presence of antiphospholipid antibodies (aPL) and thrombotic and/or adverse obstetric outcomes. The diagnosis and risk assessment of APS is challenging. This systematic review investigated if the thrombin generation (TG) assay could be helpful for APS diagnosis and risk assessment.

Methods: A systemic review was performed by searching two databases (MEDLINE and Embase) until March 31, 2022, using a search strategy with two concepts: APS and TG, and related keywords. Two reviewers independently screened the articles based on predefined inclusion and exclusion criteria. Data extraction and quality assessment with the Newcastle-Ottawa Scale (NOS) were performed independently. Synthesis Without Meta-analysis guidelines were followed for data synthesis reporting.

Results: Fourteen studies with 677 APS and 1,349 control subjects were included with variable quality according to the NOS. Twelve studies measured TG via the calibrated automated thrombogram (CAT) method using a fluorogenic substrate, whereas two used a chromogenic substrate-based TG assay. One study compared the CAT assay to the fully-automated ST Genesia® (Stago, France). Two studies initiated TG using platelet-rich plasma, whereas the rest of the studies used platelet-poor plasma. Resistance to activated protein C (aPC) was examined in ten studies. They reported a significant increase in aPC-resistance in APS patients compared to healthy controls, aPL-carriers, and thrombotic controls. Based on two studies, the prevalence of aPC-resistance was higher in APS patients compared to healthy controls and thrombotic controls with odds ratios of 5.9 and 6.8-12.8, respectively (p < 0.05). In contrast, no significant difference in aPC-resistance was found between APS patients and autoimmune disease controls. Furthermore, 7/14 studies reported TG-parameters including peak height, endogenous thrombin potential, lag time, and time to peak, but these outcomes were highly variable between studies. Furthermore, TG methodology between studies differed greatly, impacting the comparability of the studies.

Conclusion: aPC-resistance measured with TG was increased in APS patients compared to healthy and thrombotic controls, but the diagnostic and prognostic value is unclear compared to current diagnostic strategies. Studies of other TG-parameters were heterogeneous and more research is needed to identify their potential added value in APS diagnosis.

Systematic review registration: https://www.PROSPERO/, identifier: CRD42022308363.

Keywords: anitphospholipid antibodies; antiphospholid syndrome; pregnancy outcome; thrombin generation; thrombosis.

Figure 1

Flow chart of the systematic search of the literature and study selection process.

Figure 2

Effect direction plot comparing different outcomes between patient groups and control groups. Explanation: ▴: increased in patient population compared to control population; ▾: decreased in patient population compared to control population; ◄►: no significant difference between patient and control population. Control populations: (A): antiphospholipid antibody carriers; (B): thrombotic controls and control patients on vitamin K antagonist therapy; (C): autoimmune disease control group; (D): presumably healthy controls. *Thrombin generation with 1 pM TF, **5 pM TF; (1) developmental cohort, (2) validation cohort. Abbreviations: aPC-r, activated protein C resistance; APS, antiphospholipid syndrome; ETP, endogenous thrombin potential; LT, lag time; NOS, Newcastle-Ottawa Score; OAPS, obstetric APS; PH, peak height; TAPS, thrombotic APS; ttPeak, time to peak.