Current and Future Perspectives on ADAMTS13 and Thrombotic Thrombocytopenic Purpura

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a rare, relapsing, and life-threatening disorder with an annual incidence of 10 cases per million people. TTP is a thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia. The disease is caused by a severe deficiency of the enzyme ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), which can either be acquired, mainly by autoantibodies targeting ADAMTS13, or congenital due to mutations in the ADAMTS13 gene. Thanks to the establishment of national registries worldwide, fundamental and translational research, major advances have been made on the diagnosis, treatment, and fundamental understanding of TTP, since the description of the first TTP case almost 100 years ago. The introduction of therapeutic plasma exchange in the 1970s has significantly improved patient survival, but novel diagnostic assays, targeted treatments (rituximab, caplacizumab, recombinant ADAMTS13), and the unraveling of both ADAMTS13 function and TTP pathophysiology should help to further improve the patients' quality of life. However, differential diagnosis of TTP remains challenging and still a lot of questions remain unanswered to completely understand this rare and devastating disease.

Imbalance of von Willebrand factor and ADAMTS13 axis is rather a biomarker of strong inflammation and endothelial damage than a cause of thrombotic process in critically ill COVID‐19 patients

“…[9][10][11][12] between severe COVID-19-related microthrombosis and secondary TMA-like syndrome enhanced by partial consumption and/or inhibition of ADAMTS13 by inflammatory cytokines as IL-6, in line with a process similar to that observed in sepsis. 1,6 In COVID-19, a phenomenon of thrombotic pulmonary capillaritis supporting ARDS could be partially explained by the unbalance between VWF and ADAMTS13 and play a crucial role in short-term prognosis. [6][7][8][9][10][11][12] In our group of 53 critically ill patients with COVID-19, both ADAMTS13 activity and the VWF:Ag/ADAMTS13:activity ratio were correlated to mortality, in agreement with other studies.…”

“…ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats, member 13) is the specific cleaving protease for von Willebrand factor (VWF), a multimeric glycoprotein released in blood from endothelial cells and that mediates platelet adhesion and aggregation. 1 Under physiological conditions, ADAMTS13 regulates the size of VWF multimers to prevent platelet‐rich thrombi formation in the blood microvessels and it circulates in a closed conformation through a CUB‐spacer (complement component Clr/Cls, Uegf, and bone morphogenic protein 1) domains interaction, which is temporarily disrupted upon binding to VWF. 2 The pathologic development of autoantibodies to ADAMTS13 induces a severe ADAMTS13 deficiency (activity <10 IU/dl), leading to the accumulation of ultralarge VWF multimers and subsequent systemic microvascular thrombosis that causes a specific thrombotic microangiopathy (TMA) named immune‐mediated thrombotic thrombocytopenic purpura (iTTP).…”

<p>Assessment and Monitoring of Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura (iTTP): Strategies to Improve Outcomes</p>

“…Similarly, to the first episode of TTP, platelet count should be measured immediately and rapid interventions for thrombocytopenia should be performed if symptoms (bruising, dark urine, neurologic symptoms or unexplained severe fatigue) develop. 3,49 Therefore, particularly patients with a persistently low ADAMTS13 activity should avoid external triggers (infections, pregnancy, surgery) to avoid relapsing TTP. 49 Currently, clinical factors and laboratory biomarkers that could reliably predict the iTTP exacerbation and/or relapse are insufficient.…”

“…3,49 Therefore, particularly patients with a persistently low ADAMTS13 activity should avoid external triggers (infections, pregnancy, surgery) to avoid relapsing TTP. 49 Currently, clinical factors and laboratory biomarkers that could reliably predict the iTTP exacerbation and/or relapse are insufficient. ADAMTS-13 activity monitoring during the follow-up after the acute episode allows discovering patients in remission with persistent undetectable protease activity.…”

“…Besides, a reduced DNase activity in TTP patient plasma was demonstrated to result in the persistence of neutrophil extracellular traps and could act as the second hit needed to provoke an acute TTP episode, since human neutrophil peptides are also able to inhibit ADAMTS13 activity in vitro. 49,56 Rituximab is administered as a preemptive therapy for the persistence of severe ADAMTS13 deficiency associated with an increased risk of relapsed during hematological remission to ensure normalization of ADAMTS13 activity and to prevent overt relapse. 33,34 Current studies also focus on the ideal dose and the treatment scheme of rituximab in iTTP.…”