Non-ADAMTS13 Parameters Could Benefit Differential Diagnosis in TTP

Patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) could benefit from non-ADAMTS13 biomarkers being used in differential diagnosis and follow-up, according to a review published in the Journal of Clinical Medicine.

TTP is a rare disease caused by a deficiency of the ADAMTS13 enzyme, which can lead to severe thrombocytopenia, hemolytic anemia, and ischemic organ failure. A clinical diagnosis of TTP has been determined by identifying severe thrombocytopenia and microangiopathic hemolytic anemia, high levels of lactate dehydrogenase, and reduced ADAMTS13 activity. Therapeutic plasma exchange and corticosteroids have been used as standard iTTP therapy. Being able to identify the patients most at risk for relapse of TTP is a challenge due to reliable biomarkers being absent. This study aimed to review the potential of promising biomarkers that could enhance predictions of relapse.

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Deficient activity in ADAMTS13 is a risk factor of relapse of acute iTTP, which encourages the monitoring of the ADAMTS13 levels and anti-ADAMTS13 immunoglobin G (IgG). A study found that in 35 patients with iTTP in an 18-month follow-up period, elevated anti-ADAMTS13 IgG levels were linked to the absence of detectable ADAMTS13 activity; just under half of the survivors (6 of 13) with undetectable ADAMTS13 activity experienced a relapse. These findings were confirmed in another study, with positive anti-ADAMTS13 antibodies and deficiency of ADAMTS13 being linked to recurrent relapses, with the likelihood of relapse 3.6 times higher in this subset. Higher risk of relapse was found to be associated with younger age and lower ADAMTS13 activity in a third study.

The ADAMTS13 antigen is not evaluated in clinical practice on a routine basis; however, ADAMTS13 depletion is associated with the severity of iTTP, due to fatal disease outcomes and a 5-fold higher mortality rate is associated with ADAMTS13 antigen levels in the lowest quartile. Checking ADAMTS13 antigen levels could help predict disease outcome. Open ADAMTS13 conformation can also be used as biomarker to initially diagnose iTTP, both acute and subclinical.

Non-ADAMTS13 parameters could also be used to determine adverse events related to iTTP. Cardiac troponin-T and -I (cTnT and cTnI) are biomarkers used to identify myocardial injury and acute coronary syndrome. A retrospective study conducted in the United Kingdom found that 54% of patients had a positive cTnT test, half of whom had cardiac symptoms, and elevated anti-ADAMTS13 IgG was associated with a positive cTnT test of above 0.25 ng/mL; both parameters predicted mortality and morbidity in acute iTTP. Increased cTnI of more than 0.1 ng/mL was found in 78 of 133 patients with iTTP, with a cTn1 level above 0.25 ng/mL determined to be an independent factor in death (odds ratio, 2.87).

Pathophysiology of TTP has been linked to endothelial cell activation and inflammation. Proteins that are derived from endothelial cells could act as a potential biomarker for acute iTTP. The von Willebrand factor protein antigen levels were not found to be predictive of iTTP. Big endothelin-1 was linked to acute renal insufficiency, higher mortality rates in the hospital, and exacerbations of iTTP if consistently high in plasma levels. Higher plasma levels of syndecan-1 and soluble thrombomodulin were found to be associated with acute iTTP in patients who were admitted; these levels were also elevated during remission. Larger studies need to be conducted to prove effectiveness in predicting outcomes and potential relapses in iTTP.

Diagnosing iTTP and other subdiagnoses could be possible when looking into other biomarkers beyond ADAMTS13 alone. Open ADAMTS13 conformation, anti-ADAMTS13 antibody levels, and other biomarkers could help to predict disease severity as well as mortality. Further studies will need to be conducted to evaluate the usefulness of these parameters in predicting mortality and severity in iTTP.

Reference

Bonnez Q, Sakai K, Vanhoorelbeke K, et al. ADAMTS13 and non- ADAMTS13 biomarkers in immune-mediated thrombotic thrombocytopenic purpura. J Clin Med. 2023;12:6169. doi:10.3390/jcm12196169