Insights from the Hereditary Thrombotic Thrombocytopenic Purpura Registry: Discussion of Key Findings Based on Individual Cases from Switzerland

Abstract

The Hereditary TTP Registry is an international cohort study for patients with a confirmed or suspected diagnosis of hereditary thrombotic thrombocytopenic purpura (hTTP) and their family members. Hereditary TTP is an ultra-rare blood disorder (prevalence of ∼1–2 cases per million), the result of autosomal-recessively inherited congenital ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency (ADAMTS13 activity <10% of the normal), and associated with yet many unanswered questions. Until December 2017, the Hereditary TTP Registry had enrolled 123 confirmed hTTP patients. Their median age at disease onset was 4.5 years (range: 0–70) and at clinical diagnosis 16.7 years (range: 0–69), a difference that highlights the existing awareness gap in recognizing hTTP. The systematic collection of clinical data of individual patients revealed their substantial baseline comorbidities, as a consequence of recurring TTP episodes in the past. Most notable was the high proportion of patients having suffered from premature arterial thrombotic events, mainly transient ischemic attacks, ischemic strokes, and to a lesser extent myocardial infarctions. At 40 to 50 years of age and above, more than 50% of patients had suffered from at least one such event, and many had experienced arterial thrombotic events despite regular plasma infusions every 2 to 3 weeks that supplements the missing plasma ADAMTS13. The article by van Dorland et al. (Haematologica 2019;104(10):2107–2115) and the ongoing Hereditary TTP Registry cohort study were recognized with the Günter Landbeck Excellence Award at the 50th Hemophilia Symposium in Hamburg in November 2019, the reason to present the Hereditary TTP Registry in more detail here.

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

“…These aspects raise the question of the target ADAMTS13 activity to be maintained after an acute TTP event, and may propel in the future a revision of the current pre‐emptive strategies as well as clinical follow‐up and therapeutic evaluation according to underlying cardiovascular risk factors. Similar data were recently reported for cTTP patients 115,118–121 …”

“…Further, 11% of patients in the international cTTP registry had a reported transfusion‐transmitted viral disease, 115 and allergic reactions are also frequent, although manageable 111 . The recently published experience of the UK, 118 Swiss 119 and Japanese 120 TTP registries are all convergent: management standards in cTTP must be improved. RhADAMTS13 will allow refinements in the prophylactic regimens used in cTTP: a tighter prophylactic regimen with correct dosing of a pure form of ADAMTS13 will become available, may allow treatment to be continued at home, and may bring the possibility to prevent short‐term and long‐term comorbidities, as well as the possibility of applying a series of more standardized, yet personalized protocols, for example, depending on the mutations present, age of onset, or frequency of acute events 121,122 …”

Infection as Trigger for Congenital Thrombotic Thrombocytopenic Purpura in an Adult Patient

“…The estimated prevalence worldwide is unknown but is estimated to be around 16.7 cases per million [ 4 ]. Historically iTTP was described as a pentad, compromising microangiopathic hemolytic anemia, fever, neurological symptoms, renal impairment, and thrombocytopenia; but cTTP varies widely in its forms of presentation [ 1 ]. It can range from a severe disease diagnosed in early childhood to a mild disease diagnosed in adults that is classically mistaken for another cause of thrombocytopenia, most commonly ITP like in our case we reported.…”

“…Congenital thrombotic thrombocytopenic purpura (cTTP), also known as Upshaw-Schulman syndrome, is a rare disease usually diagnosed during childhood [ 1 ]. cTTP features include thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and end-organ damage [ 2 ].…”

Thrombotic microangiopathy in children

“…Its diagnosis requires confirmation of severe ADAMTS13 deficiency (plasma activity < 10%) in the absence of inhibitory antibodies (non-inhibitory antibodies may be present) and confirmed by finding a pathogenic mutation in the ADAMTS13 gene. There is often a delay in diagnosis of hTTP; the Hereditary TTP Registry [ 83 ] has enrolled more than 120 patients with mean age of presentation 4.5 years and mean age of diagnosis 16.7 years, showing the gap in knowledge regarding this disease.…”