ADAMTS13 and Non-ADAMTS13 Biomarkers in Immune-Mediated Thrombotic Thrombocytopenic Purpura

Abstract

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare medical emergency for which a correct and early diagnosis is essential. As a severe deficiency in A Disintegrin And Metalloproteinase with ThromboSpondin type 1 repeats, member 13 (ADAMTS13) is the underlying pathophysiology, diagnostic strategies require timely monitoring of ADAMTS13 parameters to differentiate TTP from alternative thrombotic microangiopathies (TMAs) and to guide initial patient management. Assays for conventional ADAMTS13 testing focus on the enzyme activity and presence of (inhibitory) anti-ADAMTS13 antibodies to discriminate immune-mediated TTP (iTTP) from congenital TTP and guide patient management. However, diagnosis of iTTP remains challenging when patients present borderline ADAMTS13 activity. Therefore, additional biomarkers would be helpful to support correct clinical judgment. Over the last few years, the evaluation of ADAMTS13 conformation has proven to be a valuable tool to confirm the diagnosis of acute iTTP when ADAMST13 activity is between 10 and 20%. Screening of ADAMTS13 conformation during long-term patient follow-up suggests it is a surrogate marker for undetectable antibodies. Moreover, some non-ADAMTS13 parameters gained notable interest in predicting disease outcome, proposing meticulous follow-up of iTTP patients. This review summarizes non-ADAMTS13 biomarkers for which inclusion in routine clinical testing could largely benefit differential diagnosis and follow-up of iTTP patients.

Pathological Mechanisms and Novel Testing Methods in Thrombotic Thrombocytopenic Purpura

“…The procedure is effective for two reasons: it removes anti-ADAMTS13 antibodies from the affected patient’s circulation and replenishes ADAMTS13 stores with donor plasma allowing UL-vWF multimer cleavage [ 8 ]. In terms of treatment, given the overwhelming preponderance of iTTP, immunosuppression is routinely initiated with corticosteroids and/or the anti-CD20 monoclonal antibody rituximab [ 1 , 7 , 16 , 17 ].…”

“…Recent reports have highlighted an additional potential mechanism resulting in TTP that is unrelated to the congenital deficiency of or antibodies to ADAMTS13. Changes in ADAMTS13 to a “closed” conformation have been linked to a non-immune form of TTP, in a proposed phenomenon of TTP of unknown pathophysiology, or uTTP ( Figure 1 ) [ 2 , 13 , 14 , 15 , 16 ]. In these cases, cTTP is not present, and antibodies to ADAMTS13 are not detected, leading to this third category [ 13 , 14 , 16 ].…”

“…Changes in ADAMTS13 to a “closed” conformation have been linked to a non-immune form of TTP, in a proposed phenomenon of TTP of unknown pathophysiology, or uTTP ( Figure 1 ) [ 2 , 13 , 14 , 15 , 16 ]. In these cases, cTTP is not present, and antibodies to ADAMTS13 are not detected, leading to this third category [ 13 , 14 , 16 ]. While the open conformation is linked to iTTP, non-immune uTTP patients present with closed ADAMTS13 [ 14 ].…”

“…Studies within the past decade have suggested Biomedicines 2024, 12, 621 2 of 11 laboratory measurements-most notably, immature platelet fraction (IPF) and absolute immature platelet count (A-IPC) tests may serve as complementary to ADAMTS13 testing, which for many institutions requires sending out testing to be performed at specialized reference laboratories, which is not ideal for a timely diagnosis [8][9][10][11][12]. Conversely, and with interesting implications for TTP pathophysiology, conformational changes in ADAMTS13 have been shown to contribute to the disease and may serve as a biomarker of disease progression or recurrence [13][14][15][16].…”