TTP: From empiricism for an enigmatic disease to targeted molecular therapies

Abstract

The 100th anniversary of the first description of Thrombotic Thrombocytopenic Purpura (TTP) as a disease by Dr. Eli Moschcowitz approaches. For many decades, TTP remained mostly a mysterious fatal condition, where diagnosis was often post-mortem. Initially a pentad of symptoms was identified, a pattern that later revealed to be fallible. Sporadic observations led to empiric interventions that allowed for the first impactful breakthrough in TTP treatment, almost 70 years after its first description: the introduction of plasma exchange and infusions as treatments. The main body of knowledge within the field was gathered in the latest three decades: patient registries were set and proved crucial for advancements; the general mechanisms of disease have been described; the diagnosis was refined; new treatments and biomarkers with improvements on prognosis and management were introduced. Further changes and improvements are expected in the upcoming decades. In this review, we provide a brief historic overview of TTP, as an illustrative example of the success of translational medicine enabling to rapidly shift from a management largely based on empiricism to targeted therapies and personalized medicine, for the benefit of patients. Current management options and present and future perspectives in this still evolving field are summarized.

FIGURE 1

A representation of current Thrombotic Thrombocytopenic Purpura (TTP) epidemiology and its main mechanisms. (A) An overview of a population of 100 TTP patients and the likely distribution of the different types of TTP is shown (adapted from reference 69). (B) The multimeric size distribution of von Willebrand factor (VWF; adapted from reference 71). (C) Comparison between normal physiologic conditions of blood flow and TTP. The basic mechanisms of disease are shown, as well as the characteristic signs and symptoms. The relative sizes of ADAMTS13, autoantibodies, VWF multimers and blood cell components is not to scale. In physiologic conditions, functional ADAMTS13 (green ADAMTS13 molecules) cleaves [unusually large (UL)]‐VWF multimers that are secreted from endothelial cells and unravel under high shear stress conditions. In TTP, ADAMTS13 is not functional (activity <10%) either due to mutations (yellow ADAMTS13 molecules)/lack of its secretion (cTTP), or because of autoantibodies that target functional ADAMTS13 and directly inhibit its activity and/or clear it from circulation (iTTP). In TTP, UL‐VWF multimers are not processed and this facilitates platelet recruitment and thrombosis within the circulation, as well as red‐blood‐cell damage (red blood cells get fragmented and will appear as schistocytes in a blood film)

FIGURE 2

The course of a patient with suspected/proven immune‐mediated Thrombotic Thrombocytopenic Purpura (iTTP) in a hospital with optimal resources. Acute stage: if the patient suffers from a thrombotic microangiopathy without any apparent cause, a clinical score should be used to estimate ADAMTS13 levels and a citrated blood sample taken for actual ADAMTS13 activity assessment at the day of presentation (Day 0). The French Score takes into account thrombocytopenia and creatinine values, scoring +1 for each if present. A score of 2 indicates high probability of ADAMTS13 < 10%. In this case, a triplet regimen with daily PEX + steroids and daily caplacizumab is instated. If the clinical score is 1, TTP should still be suspected and PEX + steroids and daily caplacizumab should be initiated and kept until the ADAMTS13 activity test results from Day 0 arrive. If ADAMTS13 ≥ 10%, this is suggestive of an alternative diagnosis. If ADAMTS13 < 10%, the diagnosis of iTTP is confirmed, and rituximab is added (usually by day 4 following PEX initiation). This regimen is kept until a clinical response ensues for two days, at which point PEX is stopped, but the remaining therapies continue, with weekly assessments of ADAMTS13 activity. Caplacizumab may be stopped once adequate ADAMTS13 responses are achieved (>20% or >10%)., Long‐term follow‐up: the focus shifts to preventing relapses and long‐term morbidity, with periodic assessments of ADAMTS13 activity (typically every three months, with pre‐emptive treatment if needed), and yearly assessments to control cardiovascular risk factors, assessment of neuropsychiatric disorders and improvement of quality of life as well as other specific assessments (e.g. pregnancy planning in the case of female patients of childbearing age)

FIGURE 3

The nature of polyclonal autoantibody mixtures in Immune‐mediated Thrombotic Thrombocytopenic Purpura (iTTP) patients and ideal characteristics of a ‘bio‐better’ ADAMTS13. The domain structure of ADAMTS13 in single letter and number codes is shown. From left to right: M, metalloprotease; D, disintegrin; T1, thrombospondin (TSP) repeat 1; C, Cys‐rich; S, spacer; T2–T8, TSP repeats 2–8; CUB‐1 and CUB‐2, complement subcomponent C1r/C1s, embryonic sea urchin protein Uegf, bone morphogenetic protein 1 domain. The general characteristics of patients' autoantibody mixtures are shown, based on compiled data shown in the supplementary data of reference . Below, the ideal characteristics of a ‘bio‐better’ ADAMTS13 are indicated with perspective of the anticipated advantages it should be able to offer over the wild‐type rhADAMTS13. Several of these advantages are, in theory, linked. Notwithstanding, the wild‐type rhADAMTS13 already promises to offer a significant reduction in the burden of care in iTTP and cTTP. Figure created with BioRender.com