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

2020 ◽  
Vol 40 (S 01) ◽  
pp. S5-S14
Author(s):  
Johanna A. Kremer Hovinga ◽  
Thomas R. Braschler ◽  
Florian Buchkremer ◽  
Stefan Farese ◽  
Heinz Hengartner ◽  
...  
Keyword(s):  
Cohort Study ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Onset ◽  
Myocardial Infarctions ◽  
Thrombocytopenic Purpura ◽  
Blood Disorder ◽  
A Disintegrin And Metalloproteinase ◽  
Systematic Collection ◽  
Plasma Infusions

AbstractThe 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.

scholarly journals Annual Incidence and Severity of Acute Episodes in Hereditary Thrombotic Thrombocytopenic Purpura

Blood ◽  
2021 ◽  
Author(s):  
Erika Tarasco ◽  
Lukas Bütikofer ◽  
Kenneth D. Friedman ◽  
James N George ◽  
Ingrid V Hrachovinova ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Onset ◽  
Premature Death ◽  
Annual Incidence ◽  
Prospective Data ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Survival Frequency ◽  
Overt Disease ◽  
Plasma Infusions

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare thrombotic microangiopathy characterized by severe congenital ADAMTS13 deficiency and recurring acute episodes causing morbidity and premature death. Information on the annual incidence and severity of acute episodes in hTTP patients is largely lacking. This study reports prospective data of 87 patients from the Hereditary TTP Registry (ClinicalTrials.gov NCT01257269) for survival, frequency and severity of acute episodes from enrollment until December 2019. The 87 patients, followed for median 4.2 years (range 0.01-15), had a median age at overt disease onset and at clinical diagnosis of 4.6 years and of 18 years (range 0.0-70 for both), respectively. Forty-three patients received regular plasma prophylaxis, while 22 did not, and treatment changed over time or was unknown in the remaining 22. Forty-three patients experienced 131 acute episodes of which 91 (69%) occurred in patients on regular prophylaxis. This resulted in an annual incidence of acute episodes of 0.36 (95%CI 0.29-0.44) with and of 0.41 (95%CI 0.30-0.56) without regular plasma treatment. More than one third of acute episodes (n=51) were documented in children &lt;10 years of age at enrollment and were often triggered by infections. Their annual incidence of acute episodes was significantly higher than in patients &gt;40 years of age (1.18 [95% CI 0.88-1.55] vs. 0.14 [95% CI 0.08-0.23]). Prophylactic plasma infusion regimens used were insufficient to prevent acute episodes in many patients. Such regimens are burdensome, caregivers, patients and their guardians are reluctant to start regular plasma infusions, from which particularly children would benefit.

Thrombotic thrombocytopenic purpura: basic pathophysiology and therapeutic strategies

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 292-299 ◽  
Author(s):  
James T. B. Crawley ◽  
Marie A. Scully
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Therapeutic Strategies ◽  
Therapeutic Approaches ◽  
Thrombocytopenic Purpura ◽  
Vessel Injury ◽  
Adamts13 Deficiency ◽  
Flowing Blood ◽  
A Disintegrin And Metalloproteinase ◽  
Anti Cd20

Abstract VWF is a multimeric plasma glycoprotein that specifically recruits platelets to sites of vessel injury. VWF multimeric size is central to this function, with larger multimers being more hemostatically active. Regulation of VWF multimeric size is mediated by the plasma metalloprotease ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motifs, member 13). This enzyme can only recognize and cleave VWF when it is unraveled by rheological shear forces of the flowing blood. After the exposure of cryptic exosites, VWF recognition by ADAMTS13 involves multiple interactions that enable the protease to cleave VWF. Loss of VWF multimer size regulation caused by severe ADAMTS13 deficiency (either inherited or acquired) is associated with the microvascular thrombotic disorder thrombotic thrombocytopenic purpura (TTP). The sequelae associated with TTP are widely thought to be linked to hyperreactive circulating VWF that cause unwanted platelet aggregation in the high shear environment of the microvasculature. Diagnosis of TTP is primarily made through a combination of symptoms, analysis of plasma ADAMTS13 activity, and detection of inhibitory anti-ADAMTS13 antibodies. Current frontline treatments for TTP include plasma exchange, which serves to remove inhibitory antibodies (in acquired TTP) and provide a source of functional ADAMTS13, and steroids to treat the autoimmune component of acquired TTP. The use of anti-CD20 therapy has also exhibited encouraging results in the treatment of acquired TTP. Newer therapeutic strategies that are currently being explored or are in development include recombinant ADAMTS13, a hyperreactive ADAMTS13 variant, and anti-VWF therapy. This review discusses the basic biochemistry of VWF and ADAMTS13, their dysfunction in TTP, and therapeutic approaches for the amelioration of TTP.

scholarly journals What's new in the diagnosis and pathophysiology of thrombotic thrombocytopenic purpura

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 631-636 ◽  
Author(s):  
J. Evan Sadler
Keyword(s):  
Renal Failure ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Case Definition ◽  
Timely Initiation ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
A Disintegrin And Metalloproteinase ◽  
Definition Of ◽  
Anuric Renal Failure

Abstract Severe ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency causes thrombotic thrombocytopenic purpura (TTP), which is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and the absence of oliguric or anuric renal failure. However, some patients with this constellation of findings do not have ADAMTS13 deficiency, and some patients with ADAMTS13 deficiency have renal failure or relatively normal blood counts. Consequently, many investigators and clinicians have incorporated severe ADAMTS13 deficiency into the case definition of TTP. This change has facilitated the timely initiation of treatment for patients with atypical clinical features who otherwise would not be recognized as having TTP. Conversely, excluding severe ADAMTS13 deficiency focuses attention on the diagnosis and treatment of other causes of thrombotic microangiopathy that require different treatment. The rapid return of ADAMTS13 data is important to make the best use of this information.

scholarly journals How I treat refractory thrombotic thrombocytopenic purpura

Blood ◽  
2015 ◽  
Vol 125 (25) ◽  
pp. 3860-3867 ◽  
Author(s):  
Farzana A. Sayani ◽  
Charles S. Abrams
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Clinical Symptoms ◽  
Thrombocytopenic Purpura ◽  
New Therapeutic Approaches ◽  
Number Of Patients ◽  
A Disintegrin And Metalloproteinase ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) without an obvious cause, and may include fever, mild renal failure, and neurologic deficits. It is characterized by a deficiency of the von Willebrand factor (VWF) cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase, with a thrombospondin type 1 motif, member 13), resulting in formation of microthrombi in the high sheer environment of the microvasculature. This causes microvascular occlusion, MAHA, and organ ischemia. Diagnosis is based on the presence of clinical symptoms, laboratory aberrations consistent with MAHA, decreased ADAMTS13 activity, and possibly presence of anti-ADAMTS13 autoantibodies. Upfront treatment of acute TTP includes plasma exchange and corticosteroids. A significant number of patients are refractory to this treatment and will require further interventions. There are limited data and consensus on the management of the refractory TTP patient. Management involves simultaneously ruling out other causes of thrombocytopenia and MAHA, while also considering other treatments. In this article, we describe our management of the patient with refractory TTP, and discuss use of rituximab, increased plasma exchange, splenectomy, and immunosuppressive options, including cyclophosphamide, vincristine, and cyclosporine. We also review recent evidence for the potential roles of bortezomib and N-acetylcysteine, and explore new therapeutic approaches, including recombinant ADAMTS13 and anti-VWF therapy.

scholarly journals Thrombotic thrombocytopenic purpura after ChAdOx1 nCoV-19 vaccine

2021 ◽  
Vol 14 (10) ◽  
pp. e246049
Author(s):  
Hui Ping Lee ◽  
Veena Selvaratnam ◽  
Jay Suriar Rajasuriar
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Blood Film ◽  
Indian Woman ◽  
Thrombocytopenic Purpura ◽  
First Case ◽  
Immune Mediated ◽  
Peripheral Blood Film ◽  
A Disintegrin And Metalloproteinase ◽  
The Brain

A 50-year-old Indian woman presented with acute dysphasia, left upper limb numbness and thrombocytopenia 12 days after receiving the ChAdOx1 nCoV-19 vaccine (AstraZeneca/Vaxzevria). MRI of the brain was unremarkable. Microangiopathic haemolytic anaemia with thrombocytopenia was noted on her peripheral blood film. A diagnosis of thrombotic thrombocytopenic purpura (TTP) was confirmed through the findings of absent ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity and markedly raised titre of ADAMTS13 autoantibodies. Prompt treatment with plasma exchange, adjunctive steroids and rituximab was commenced. A remission of TTP was achieved and she was discharged 3 weeks after admission. While other immune-mediated conditions have been documented after receipt of the vaccine, this report highlights the first case of immune-mediated TTP diagnosed after administration of the ChAdOx1 nCoV-19 vaccine.

Exome Sequencing Identifies Abnormalities in Glycosylation and ANKRD36C in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura

2020 ◽  
Author(s):  
Malay Kumar Basu ◽  
Felipe Massicano ◽  
Lijia Yu ◽  
Konstantine Halkidis ◽  
Vikram Pillai ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Onset ◽  
Protein Glycosylation ◽  
Healthy Controls ◽  
Major Pathway ◽  
Thrombocytopenic Purpura ◽  
Hematological Disorders ◽  
Blood Disorder ◽  
Immune Mediated

Abstract Background Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder, resulting from autoantibodies against ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). However, the mechanism underlying anti-ADAMTS13 autoantibody formation is not known, nor it is known how genetic aberrations contribute to the pathogenesis of iTTP. Methods Here we performed whole exome sequencing (WES) of DNA samples from 40 adult patients with iTTP and 15 local healthy subjects with no history of iTTP and other hematological disorders. Results WES revealed variations in the genes involved in protein glycosylation, including O-linked glycosylation, to be a major pathway affected in patients with iTTP. Moreover, variations in the ANKRD gene family, particularly ANKRD36C and its paralogs, were also more prevalent in patients with iTTP than in the healthy controls. The ANKRD36 family of proteins have been implicated in inflammation. Mass spectrometry revealed a dramatic alternation in plasma glycoprotein profile in patients with iTTP compared with the healthy controls. Conclusion Altered glycosylation may affect the disease onset and progression in various ways: it may predispose patients to produce ADAMTS13 autoantibodies or affect their binding properties; it may also alter clearance kinetics of hemostatic and inflammatory proteins. Together, our findings provide novel insights into plausible mechanisms underlying the pathogenesis of iTTP.

scholarly journals Anti-ADAMTS13 autoantibody profiling in patients with immune-mediated thrombotic thrombocytopenic purpura

2021 ◽  
Vol 5 (17) ◽  
pp. 3427-3435 ◽  
Author(s):  
Kadri Kangro ◽  
Elien Roose ◽  
Bérangère S. Joly ◽  
György Sinkovits ◽  
Tanja Falter ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Acute Phase ◽  
Clinical Data ◽  
Epitope Mapping ◽  
Thrombocytopenic Purpura ◽  
Immune Mediated ◽  
Number Of Patients ◽  
Large Cohort Study ◽  
A Disintegrin And Metalloproteinase

Abstract Anti-A Disintegrin and Metalloproteinase with a ThromboSpondin type 1 motif, member 13 (ADAMTS13) autoantibodies cause a severe ADAMTS13 deficiency in immune-mediated thrombotic thrombocytopenic purpura (iTTP). ADAMTS13 consists of a metalloprotease (M), a disintegrin-like (D) domain, 8 thrombospondin type 1 repeats (T1-T8), a cysteine-rich (C), a spacer (S), and 2 CUB domains (CUB1-2). We recently developed a high-throughput epitope mapping assay based on small, nonoverlapping ADAMTS13 fragments (M, DT, CS, T2-T5, T6-T8, CUB1-2). With this assay, we performed a comprehensive epitope mapping using 131 acute-phase samples and for the first time a large group of remission samples (n = 50). Next, samples were stratified according to their immunoprofiles, a field that is largely unexplored in iTTP. Three dominant immunoprofiles were found in acute-phase samples: profile 1: only anti-CS autoantibodies (26.7%); profile 2: both anti-CS and anti-CUB1-2 autoantibodies (12.2%); and profile 3: anti-DT, anti-CS, anti-T2-T5, anti-T6-T8, and anti-CUB1-2 autoantibodies (8.4%). Interestingly, profile 1 was the only dominant immunoprofile in remission samples (52.0%). Clinical data were available for a relatively small number of patients with acute iTTP (&gt;68), and no correlation was found between immunoprofiles and disease severity. Nevertheless, profile 1 was linked with younger and anti-T2-T5 autoantibodies with older age and the absence of anti-CUB1-2 autoantibodies with cerebral involvement. In conclusion, identifying acute phase and remission immunoprofiles in iTTP revealed that anti-CS autoantibodies seem to persist or reappear during remission providing further support for the clinical development of a targeted anti-CS autoantibody therapy. A large cohort study with acute iTTP samples will validate possible links between immunoprofiles or anti-domain autoantibodies and clinical data.

scholarly journals A Case of Thrombotic Thrombocytopenic Purpura without Pathognomonic Schistocytes

2021 ◽  
Vol 11 (2) ◽  
pp. 223-227
Author(s):  
Kevin Yu ◽  
Min Yan
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Blood Smear ◽  
Clinical Manifestations ◽  
Atypical Presentation ◽  
Thrombocytopenic Purpura ◽  
Activity Awareness ◽  
A Disintegrin And Metalloproteinase ◽  
Timely Treatment ◽  
Blood Smear Review

Patients diagnosed with thrombotic thrombocytopenic purpura (TTP) typically present with microangiopathic hemolytic anemia (MAHA) and thrombocytopenia; these two clinical manifestations were often believed to be essential indicators of TTP. However, such indicators are not always present in every case. Here, we present a patient affected by TTP but showing no distinctive schistocytes on blood smear review. TTP was diagnosed through a critically low level of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) activity. Awareness of such an atypical presentation of TTP is essential for timely treatment to prevent serious and even fatal outcomes for patients.

Congenital ADAMTS-13 deficiency presenting as life-threatening thrombosis during pregnancy

2021 ◽  
Vol 14 (8) ◽  
pp. e239901
Author(s):  
Faheema Hasan ◽  
Anshul Gupta ◽  
Dinesh Chandra ◽  
Soniya Nityanand
Keyword(s):  
Late Presentation ◽  
Fresh Frozen Plasma ◽  
Artery Thrombosis ◽  
Fresh Frozen ◽  
Life Threatening ◽  
A Disintegrin And Metalloproteinase ◽  
Thrombospondin Type 1 Repeats ◽  
Frozen Plasma ◽  
Plasma Infusions

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterised by thrombocytopenia, microangiopathic haemolytic anaemia and microvascular thrombosis. Congenital TTP accounting for less than 5% of all TTP cases can have a late presentation in adulthood mostly triggered by predisposing factors such as infection, pregnancy and inflammation. We present a case of a 23-year-old woman who presented to us in the postpartum period with mesenteric artery thrombosis with infarcts and later was diagnosed as a case of TTP based on congenital a disintegrin and metalloproteinase with thrombospondin type 1 repeats 13 (ADAMTS-13) deficiency detected on ADAMTS-13 levels and gene sequencing. She was successfully managed initially with therapeutic plasma exchanges and is now on prophylactic fortnightly fresh frozen plasma infusions at 15 mL/kg body weight and continues to be in remission.

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