Acquired thrombotic thrombocytopenic purpura in a patient with plasmodium vivax malaria: A case report.

Acquired thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening disorder characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ damage. We present the case of a 71-year-old man initially diagnosed with malaria-like symptoms and displaying markers of microangiopathic hemolytic anemia, severe thrombocytopenia, renal injury, and neurological impairment. Despite antimalarial treatment, acquired TTP was suspected. Plasma exchange and immunosuppressive therapy led to clinical improvement, normalizing the platelet count and hemolytic profile. Diagnostic confirmation revealed significantly reduced ADAMTS13 levels. Following the proposed treatment, the patient's ADAMTS13 levels normalized. This case illustrates acquired TTP linked to uncomplicated Plasmodium vivax malaria.

Thrombotic Thrombocytopenia Purpura (TTP) following emergent aortic valve replacement after a complicated TAVR procedure: a case report and review of the literature.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare hematological disorder. The occurrence of TTP subsequent to an emergent aortic valve replacement after a TAVR procedure is exceedingly uncommon with only a few reported cases worldwide. CASE PRESENTATION: We report the case of a 70-year-old female patient diagnosed with aortic insufficiency. Following a transcatheter aortic valve replacement, she underwent emergency aortic valve replacement under cardiopulmonary bypass on the subsequent day due to heart valve displacement. The postoperative diagnosis revealed TTP and symptomatic treatment involving plasma exchange was administered. After demonstrating steady improvement, the patient was eventually discharged. CONCLUSION: Aortic valve replacement after TAVR is a high-risk procedure and increases susceptibility for developing secondary TTP. The diagnosis and treatment of secondary TPP is considerably challenging, and early diagnosis with symptomatic treatment including plasma exchange can increase patient survival.

ADAMTS13 in the New Era of TTP.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening, often immune-mediated disease that affects 2-13 persons per million per year. Hemolytic anemia, thrombocytopenia, and end-organ damage due to the formation of microthrombi are characteristic of TTP. ADAMTS13 is a disintegrin, metalloproteinase, cleaving protein of von Willebrand factor (VWF) that processes the VWF multimers to prevent them from interacting with platelets and, in turn, to microvascular thrombosis. Prompt diagnosis of TTP is critical yet challenging. Thrombotic microangiopathies have similar clinical presentation. Measurement of ADAMTS13 activity helps in the differential diagnosis. Less than 10% ADAMTS13 activity is indicative of TTP. Laboratory ADAMTS13 activity assays include incubating the test plasma with the substrate (full-length VWM multimers) and detection with direct or indirect measurement of the cleavage product. The purpose of this study is to examine the diagnostic potential, advantages, and weaknesses of the ADAMTS13 potency in TTP.

Longitudinal characterization of symptoms, healthcare resource utilization, and costs among people with thrombotic thrombocytopenic purpura compared with non-thrombotic thrombocytopenic purpura controls.

AIMS: Thrombotic thrombocytopenic purpura (TTP) is an ultra-rare blood disorder, characterized by severe ADAMTS13 deficiency. Affected individuals present with potentially life-threatening acute events and may experience sub-acute and chronic TTP manifestations often resulting in long-term organ damage. Incremental symptom prevalence before, during, and after an acute event as well as healthcare resource utilization (HCRU) and costs during and after an acute event were compared between people with TTP and matched non-TTP controls. METHODS: This retrospective, matched study used data from Merative MarketScan Commercial Database and Medicare Supplemental Database (from January 1, 2008, through September 30, 2021) to identify people with TTP (inpatient diagnosis for "thrombotic microangiopathy (TMA)" or "congenital TTP," and ≥1 claim for plasma exchange or infusion). People with TTP were matched (1:2) with non-TTP controls on age, sex, geographic region, index year, and select Elixhauser comorbidities. RESULTS: 255 people with TTP were matched with 510 non-TTP controls. Both cohorts had a mean age of 43.9 years; 71% were female. Overall, more people with TTP reported symptoms compared with non-TTP controls prior to (51% vs 43%), during (99% vs 52%), and after an acute event (85% vs 50%; p < 0.05 for all periods). Symptom prevalence decreased following an acute event compared with during an acute event, but remained high-85% of people with TTP experienced symptoms compared with 50% of non-TTP controls. HCRU and mean costs per patient per month were significantly higher in all care settings among people with TTP compared with non-TTP controls (p < 0.05). LIMITATIONS: Identification of patient populations may have been limited due to coding errors, as the data were obtained from an administrative claims database. CONCLUSIONS: TTP is associated with a substantial symptom burden and increased costs and HCRU during and up to almost a year after acute events, demonstrating the longitudinal burden of this disease.

Clinical, biological, prognostic characteristics of patients with immune-mediated thrombotic thrombocytopenic purpura and Sjögren's disease.

OBJECTIVES: The association between immune-mediated thrombotic thrombocytopenic purpura (iTTP) and Sjögren disease (SjD) has been poorly investigated. This study presents the first retrospective cohort of iTTP-SjD aiming to identify risk factors for iTTP occurrence in SjD patients and examine their clinical course. METHODS: Patients with iTTP-SjD were identified within the French TTP Registry based on American College of Rheumatology/European League Against Rheumatism 2016 criteria. A comparative analysis was conducted with two control groups comprising primary SjD (pSjD) patients from the French ASSESS cohort and idiopathic iTTP patients from the French TTP Registry. Demographic, clinical and biological data were retrospectively collected. RESULTS: Thirty iTTP-SjD patients were included and compared with 65 pSjD and 45 idiopathic iTTP patients. The majority of iTTP-SjD patients (n=18) were diagnosed with SjD at the time of iTTP diagnosis. In comparison with the pSjD cohort, iTTP-SjD patients were diagnosed with SjD at a younger age (p=0.039) and showed a higher prevalence of anti-SjS-related antigen A antibody positivity and xerostomia (p=0.015, p=0.035, respectively). EULAR Sjogren's Syndrome Disease Activity Index showed similar activity levels between the two groups. iTTP-SjD patients were treated with plasma exchange (n=28), corticosteroids, rituximab (n=19) and caplacizumab (n=3). In comparison with the idiopathic iTTP cohort, mortality rates (log-rank tests, p=0.228), biological and clinical iTTP relapses (multivariate analysis, p=0.181) were comparable and short-term outcomes (survival at day 30, relapse) were favourable. CONCLUSION: iTTP can be a rare complication in patients with SjD. Further studies involving larger cohorts and long-term follow-up are warranted to confirm these findings and to explore the efficacy of immunomodulators and caplacizumab in iTTP-SjD patients.

Vascular endothelial-cadherin is involved in endothelial cell detachment during thrombotic thrombocytopenic purpura.

BACKGROUND: Immune thrombotic thrombocytopenic purpura (i-TTP) is a life-threatening thrombotic microangiopathy linked to ADAMTS-13 deficiency. It has long been assumed that the activation of endothelial cells is the triggering factor for the thrombotic thrombocytopenic purpura crisis. Circulating endothelial cells (CECs) have been shown to be a biomarker of vascular damage and are associated with the clinical severity of i-TTP. However, the mechanisms leading to endothelial cell detachment remain unclear. OBJECTIVES: We investigated junctional destabilization the mechanisms underlying cell detachment in thrombotic thrombocytopenic purpura. METHODS: We quantified CECs in i-TTP patients and investigated the effect of plasmas in vitro by measuring phosphorylation and internalization of vascular endothelial (VE)-Cadherin and in vivo in a vascular permeability model. RESULTS: In plasma from i-TTP patients, we show that CEC count is associated with severity and correlated to intracellular calcium influx (P < .01). In vitro, serum from i-TTP patients induced stronger detachment of human umbilical vein endothelial cells than serum from control patients (P < .001). Plasma from i-TTP patients induced a higher calcium-dependent phosphorylation (P < .05) and internalization (P < .05) of VE-cadherin compared with plasma from control patients. This effect could be reproduced by immunoglobulin (Ig)G fraction isolated from patient plasma and, in particular, by the F(ab)'2 fragments of the corresponding IgG. In addition, subcutaneous injection of i-TTP plasma into mice resulted in higher vascular permeability than plasma from control patients. An inhibitor of endothelial calcium influx, ITF1697, normalized this increase in permeability. CONCLUSION: Our results suggest that plasma-induced endothelial activation also leads to an increase in vascular permeability. They contribute to the understanding of the mechanisms behind the presence of elevated CECs in patients' blood by linking endothelial activation to endothelial injury.

Thrombotic thrombocytopenic purpura: 100 years of research on Moschcowitz syndrome.

ABSTRACT: In the 100 years since Eli Moschcowitz reported the first case of thrombotic thrombocytopenic purpura (TTP), there has been remarkable awareness and progress in the diagnosis and management of this rare blood disorder. This progress initially was the result of careful clinical observations followed by well thought-out therapeutic interventions, with dual goals of both improving outcomes and discerning the pathophysiology of TTP. The discovery of the ADAMTS13 protease set in motion the efforts to more accurately define the specific etiologies of thrombotic microangiopathies (TMAs) based on objective, scientific data rather than clinical characterizations alone. This accurate differentiation led to better and more revealing clinical trials and advancements in the treatment of TTP and other TMAs. Further advances followed and included improvements in immune-suppressive therapy and targeted therapies of immune-mediated TTP (iTTP; caplacizumab) and congenital TTP (cTTP; recombinant ADAMTS13). The longitudinal study of patients with TTP revealed the unexpected risk for long-term complications in both patients with iTTP and those with cTTP in remission. Ongoing studies aim to further understand the prevalence, mechanisms, and appropriate screening for these mood disorders, neurocognitive deficits, and cardiovascular complications that develop at remarkably high rates and are associated with a decreased life expectancy. These discoveries are a result of the collaborative efforts of investigators worldwide that have been fostered by the frequent interactions of investigators via the International TTP Working Group meetings and TMA workshops held regularly at international meetings. These efforts will support the rapid pace of discovery and improved understanding of this rare disease.

Caplacizumab in pediatric immune thrombotic thrombocytopenic purpura: the UK TTP Registry experience.

ABSTRACT: Pediatric thrombotic thrombocytopenic purpura (TTP) is an ultrarare disease. Immune TTP (iTTP) is driven by anti-ADAMTS13 autoantibodies causing an imbalanced von Willebrand factor (VWF):ADAMTS13 axis, and rarer still in children, but potentially life-threatening. Caplacizumab is licensed for iTTP treatment in adults and adolescents aged ≥12 years who weigh ≥40 kg. There is a need to clarify whether caplacizumab can be used in younger children. We retrospectively described caplacizumab use in 16 patients under 18 years of age from the UK TTP Registry, including 4 children aged <12 years. For patients weighing <40 kg (n = 3), caplacizumab was dosed at 5 mg once dailyThe youngest patient was 33 months old at diagnosis. Plasma exchange (PEX) was used in 15 patients, with a median of 5 exchanges required before platelet count normalization (range, 2-9). One patient was managed without PEX. All patients achieved normalization of platelet count (median, 5.5 days; range, 3-28) and ADAMTS13 activity (median, 35 days; range, 8-149), with a median hospital admission of 11 days (range, 5-26). There were no refractory patients. One patient relapsed 9 months after presentation. Bleeding requiring VWF supplementation and reduction of caplacizumab use occurred in 1 patient with severe epistaxis, with no significant intracranial or gastrointestinal bleeding. We demonstrated the efficacy and safety of caplacizumab in the pediatric population, which is synonymous with the adult trial data: primarily, reduction of PEX compared with the precaplacizumab era. This has implications for the intensification and duration of admission, particularly relevant in pediatric care.

[Advances in the treatment of thrombotic thrombocytopenic purpura].

Thrombotic thrombocytopenic purpura (TTP) is a fatal thrombotic disease caused by a marked decrease in the activity of ADAMTS13, a von Willebrand factor cleaving protease. In congenital TTP, ADAMTS13 activity is decreased by an abnormality in ADAMTS13, and in acquired TTP, by anti-ADAMTS13 autoantibody. Death from thrombosis in the acute phase has been an issue with conventional treatment of acquired TTP by plasma exchange or immunosuppressive therapy. However, the advent of caplacizumab, an anti-VWF nanobody, has made it possible to suppress thrombus formation and is expected to improve survival rates. In addition, some case series have shown the efficacy of caplacizumab without plasma exchange for acquired TTP, and this approach is being investigated in clinical trials. Fresh-frozen plasma is transfused to supply ADAMTS13 for congenital TTP, but frequent transfusions over a long period of time can lead to problems such as infection and allergic reactions. Novel therapies such as recombinant ADAMTS13 products and gene therapy are now under development, and show promise for future clinical use.

Identification of HLA alleles involved in immune thrombotic thrombocytopenic purpura patients from Turkey.

Thrombotic thrombocytopenic purpura (TTP) is one of the rare group disorders classified as thrombotic microangiopathies (TMAs). Approximately 90% of TTP developed immune-mediation by the formation of antibodies against the enzyme ADAMTS-13. The exact cause is unknown. To establish an association between human leukocyte antigen (HLA) and autoimmune basis, as susceptibility or protection against the disease, we contributed a study aiming to evaluate the role of HLA in immune-mediated TTP (iTTP). Considering epidemiological factors such as age, sex, ethnicity, and geographical origins, we contributed the study in our country, Turkey, which consist of a very heterogeneous population. Patients' data collection was retrospectively from electronic database on two University hospitals having big therapeutic apheresis service. Control arm was healthy people registered as stem cell donors matched in terms of age and sex. The frequency of HLA-DRB1 and HLA-DQB1 alleles between acquired TTP and the control group was compared using the chi-square method. Yates correction and logistic regression were performed on these results. A total of 75 iTTP patients and 150 healthy individuals enrolled to the study. HLA-DRB1∗11, HLA-DQB1∗03, HLA-DRB1∗11:01, HLA-DRB1∗14:01, HLA-DRB1∗13:05, HLA-DRB1∗11 + HLA-DQB1∗03 allele pair and HLA-DRB1∗15 + HLA- DQB1∗06 were proved to be susceptibility allele pairs for iTTP. HLA-DRB1∗15, HLA-DRB1∗01:01, HLA-DRB1∗07:01, HLA-DRB1∗13:01, HLA-DRB1∗14:54, HLA-DQB1∗05:01, HLA-DQB1∗02:02 and HLA-DRB1∗07 + HLA-DQB1∗02 allele pair were found to be protective against iTTP. Our findings support an association with iTTP across very heterogenous populations in Turkey.

Acquired immune thrombotic thrombocytopenic purpura (TTP) associated with inactivated COVID-19 vaccine CoronaVac.

Corona virus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected the whole world. Acquired thrombotic thrombocytopenic purpura (TTP) has been reported after administration of mRNA- or adenoviral vector-based COVID-19 vaccines, including Ad26.COV2-S, BNT162b2, mRNA-1273, and ChAdOx1 nCov-19. However, whether inactivated vaccines, such as CoronaVac, could cause TTP and whether the symptoms in TTPs caused by inactivated vaccines are different from previously reported cases are unknown. In this study, two cases were reported. Both cases developed TTP after the second CoronaVac vaccination shot, but not the first. They demonstrated symptoms of fever, neurological abnormalities, renal dysfunction, thrombocytopenia, and hemolysis. Both patients achieved complete remission through several sessions of plasma exchanges and immune suppression. The incidence of TTP in Nanjing area was analyzed. The number of patients with TTP was 12 in 2019, 6 in 2020, 16 in 2021, and 19 in 2022. To the authors' knowledge, this report is the first report of TTP associated with inactivated COVID-19 vaccine (CoronaVac). The rarity and delayed onset may be due to the relatively milder immune response caused by the inactivated vaccines than mRNA-based ones. Timely plasma exchange is a vital treatment for CoronaVac-related TTP, similar to activated vaccine-related TTP.

Global prevalence of hereditary thrombotic thrombocytopenic purpura determined by genetic analysis.

ABSTRACT: Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare autosomal recessive, life-threatening disorder caused by a severe deficiency of the plasma enzyme, ADAMTS13. The current estimated prevalence of hTTP in different regions of the world, 0.5 to 2.0 patients per million, is determined by the frequency of diagnosed patients. To evaluate more accurately the worldwide prevalence of hTTP, and also the prevalence within distinct ethnic groups, we used data available in exome and genome sequencing of 807 162 (730 947 exomes, 76 215 genomes) subjects reported recently by the Genome Aggregation Database (gnomAD-v4.1). Among 1 614 324 analyzed alleles in the gnomAD population we identified 6321 distinct ADAMTS13 variants. Of these, 758 were defined as pathogenic; 140 (18%) variants had been previously reported and 618 (82%) were novel (predicted as pathogenic). In total 10 154 alleles (0.6%) were carrying the reported or predicted pathogenic variants; 7759 (77%) with previously reported variants. Considering all 758 pathogenic variants and also only the 140 previously reported variants, we estimated a global hTTP prevalence of 40 and 23 cases per 106, respectively. Considering only the 140 previously reported variants, the highest estimated prevalence was in East Asians (42 per 106). The estimated prevalences of other populations were: Finnish, 32 per 106; non-Finnish Europeans, 28 per 106; Admixed Americans, 19 per 106; Africans/African Americans, 6 per 106; and South Asians, 4 per 106. The lowest prevalences were Middle Eastern, 1 per 106 and Ashkenazi Jews, 0.7 per 106. This population-based genetic epidemiology study reports that hTTP prevalence is substantially higher than the currently estimated prevalence based on diagnosed patients. Many patients with hTTP may not be diagnosed or may have died during the neonatal period.

Plasma exchange in thrombotic thrombocytopenic purpuras.

INTRODUCTION: Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal hematological disorder that requires urgent treatment. Once the diagnosis has been made, plasma exchange (PE) must be started immediately and until a response is obtained. AIM: Evaluate PE in terms of responses and complications in the treatment of TTP. METHODS: This was a monocentric, descriptive, retrospective study including patients in whom TTP was diagnosed and treated with plasmapheresis in the clinical hematology department at Aziza Othmana Hospital, between January 2010 and December 2020. RESULTS: Our study included 26 patients. PE was initiated within a median of 1 day. The rhythm of exchanges was daily in 22 patients. Twenty PE-related complications were noted, hypocalcemia being the most frequent (30%). CR was achieved in 15 patients after PE alone. Nine patients were refractory, and six received 2nd-line treatment, with CR achieved in five patients. Relapse was noted in six patients (40%). They were treated by PE and only one patient received rituximab. Four patients had a response. The overall response rate was 69% and overall mortality was 30%. OS at 2 years was 68,3% and RFS was 84,4%. Factors associated with the achievement of CR were the fall in LDH at D5 of treatment (p=0,027,OR=0,59 ;IC 95%[0,32-1,08]) and the daily rhythm of PE (p=0,005, OR=0,35; IC 95%[0,14-0,91]). CONCLUSION: Our results were comparable to those of the literature, but the rate of refractory disease was higher. Rituximab may enhance our results.

Atypical Presentations of Pediatric-acquired Thrombotic Thrombocytopenic Purpura.

BACKGROUND: Immune thrombotic thrombocytopenic purpura (iTTP) in children is a rare, severe thrombotic microangiopathy. This condition is characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia due to reduced activity of the von Willebrand factor-cleaving protease ADAMTS13. METHODS: A retrospective case series evaluating data collected from the medical files of 4 children diagnosed with iTTP. RESULTS: The presented case series depicts a variety of iTTP presentations: 1 case of primary iTTP, 1 case induced by Shiga toxin, 1 associated with RAS-associated autoimmune leukoproliferative disease (RALD), and 1 initial manifestation of systemic lupus erythematosus (SLE). Notably, 2 patients recovered without undergoing plasma exchange. CONCLUSION: Early ADAMTS13 testing in children with unexplained hemolysis or thrombocytopenia is crucial. The diverse underlying causes, including infections and autoimmune disorders, underscore the complexity of iTTP in the pediatric population. These cases highlight the necessity for personalized treatment approaches that consider each patient's unique clinical situation and potential alternatives or modifications to conventional therapeutic regimens.