Analysis of clinical factors in first diagnosis of immune thrombotic thrombocytopenic purpura with report of 6 cases

Analysis of clinical factors in first diagnosis of immune thrombotic thrombocytopenic purpura with report of 6 cases | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Analysis of clinical factors in first diagnosis of immune thrombotic thrombocytopenic purpura with report of 6 cases Wang Lingyu, Shen Weizhang, Ren Lishen, Tan Lei, Li Jinliang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4464305/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective This study aims to investigate the clinical characteristics, timing of intervention, diagnostic and treatment options, and prognostic factors in patients with immune thrombotic thrombocytopenic purpura (iTTP).Methods: We conducted a retrospective analysis of iTTP patients who visited the Second Hospital of Jilin University from January 2020 to April 2023, encompassing individuals with complete clinical data. The analysis included an examination of clinical manifestations and auxiliary test results.Results: The study involved 6 patients (5 males, 1 female) with an age range of 29–84 years, and a median age of 58 years. Common clinical manifestations comprised thrombocytopenia, hematuria, soy sauce-colored urine, as well as neurological and psychiatric symptoms. All six patients underwent treatment with therapeutic plasma exchange(TPE), with three of them also receiving rituximab (3/6). The follow-up period ranged from 1 to 21 months, with a median of 10 months, concluding in April 2023. Of the six cases, three patients survived, while the remaining three succumbed in March 2021, July 2022, and March 2023, respectively.Conclusion: TTP diagnosis is often delayed due to its nonspecific clinical presentation. Accurate clinical diagnosis of TTP relies on assessing ADAMTS13 activity levels and genetic testing. Following PLASMIC-S guidelines, immediate plasma exchange and glucocorticoid therapy are recommended once diagnosis is suspected. Additionally, the evolving clinical landscape has seen an increasing number of patients benefiting from a combination of anti-CD20 monoclonal antibodies and other novel drugs. This expanding repertoire of treatment options enhances the multidisciplinary and comprehensive diagnostic and therapeutic strategy for iTTP. thrombotic thrombocytopenic purpura treatment clinical analysis plasma exchange rituximab Figures Figure 1 Figure 2 Figure 3 Introduction Thrombotic thrombocytopenic purpura (TTP) is a rare and serious hematologic disorder, typically occurring at an incidence of approximately 2-6 cases per million people 1 . The classical clinical manifestations of TTP encompass microangiopathic hemolysis, thrombocytopenia, neurologic symptoms, fever, and renal damage, collectively forming the Pentalogy. Some patients may exhibit only the initial three symptoms, recognized as trichotillomania. Hereditary TTP, also known as congenital thrombotic thrombocytopenic purpura (cTTP), results from a severe deficiency of plasma ADAMTS5 activity due to mutations in ADAMTS13. In contrast, iTTP, triggered by immune-mediated autoantibodies inhibiting plasma ADAMTS6 activity, is characterized by low platelet counts, anemia, and microvascular thrombosis. The underlying mechanism in TTP involves excessive platelet aggregation in multiple organs, leading to the accumulation of unfolded, high-molecular-weight vascular hemophilic factor multimers in plasma, causing a significant increase in shear stress. The resulting inability to process these multimers into smaller, less adhesive forms is associated with ADAMTS13 dysfunction. ADAMTS1 deficiency may stem from mutations in the encoding gene or acquired autoantibodies, influencing enzyme function through direct neutralization or a conditioning process involving immune complex formation with ADAMTS2, subsequently cleared by phagocytes 2 . Studies indicate that 33%-90% of TTP patients exhibit severe ADAMTS13 deficiency, while ADAMTS4 activity is typically normal or only slightly reduced in patients with other causes of thrombocytopenia 2 . In this report, we present clinical data from six iTTP patients treated at the Second Hospital of Jilin University between January 2020 and April 2023. Our analysis, in conjunction with existing literature, explores their clinical manifestations, laboratory and imaging characteristics, pathological features, diagnosis, and treatment. By discussing clinicopathological features and prognostic factors, we aim to enhance the understanding of TTP and contribute to the broader knowledge of this disease. Information and Methods 1.1 General Information The retrospective analysis involved the clinical data of six patients diagnosed with TTP who sought medical care at the Second Hospital of Jilin University between January 2020 and April 2023. The cohort comprised 5 males (83.33%) and 1 female (16.67%), with ages ranging from 29 to 84 years and a median age of 58 years. Descriptive analysis was applied to all cases, and confirmation of diagnosis was based on laboratory examination, peripheral blood smear, and ADAMTS13 testing. Retrospective analysis encompassed gender, age, clinical manifestations, accompanying symptoms, laboratory and imaging test results, treatment modalities, and prognosis for each patient. 1.2 Clinical Manifestations All six patients exhibited common features, including thrombocytopenia, microangiopathic hemolytic anemia, and neuropsychiatric symptoms. Specifically, 4 cases (66.67%) manifested renal function impairment, while 2 cases (33.33%) presented with fever. Among the cases, 2 showed the typical "pentad" manifestations, 2 displayed "quadruple" manifestations, and 2 presented with "triple" manifestations. Further details can be found in Table 1 . Table 1 Clinical information of TTP patients No. Gender Age Time of onset Thrombocytopenia MAHA Neurological abnormalities Fever Impaired kidney function 1 F 84 2021-03-27 Y Y Y N Y 2 M 56 2023-03-07 Y Y Y N Y 3 F 29 2022-06-07 Y Y Y N N 4 F 72 2022-07-12 Y Y Y N N 5 F 60 2023-02-15 Y Y Y Y Y 6 F 47 2021-07-09 Y Y Y Y Y Notes: M:male; F:female;Y:yes;N:no 1.3 Laboratory, Imaging, and Other Examinations All 6 patients underwent peripheral blood smear examinations, with each smear counting 1,000 erythrocytes. The results revealed varying numbers of broken erythrocytes, indicating different degrees of heterogeneous erythrocytosis. This phenomenon is primarily attributed to the formation of broken erythrocytes and can be observed as tear drop-shaped cells, scattered lobes of erythrocytes, among other manifestations.Typical peripheral blood smears exhibited the presence of broken red blood cells, as highlighted by the arrows in Fig. 1. Red arrow indicated the schistocytes. Figure 1 Fragmented Erythrocytes in Peripheral Blood Smears of iTTP Patients All patients exhibited mild personality changes and neuropsychiatric symptoms. Among them, four cases presented imaging changes, with one case not undergoing head imaging. Among the patients who underwent head CT examination (n = 3), multiple punctate, patchy, and blurred low-density shadows were observed. Two cases that underwent magnetic head examination showed new-onset speckled or patchy high signal, with the ADC map indicating low signal. These manifestations posed challenges in distinguishing them from lacunar cerebral infarction, and were considered to be associated with acute microvascular thrombosis, albeit lacking diagnostic specificity. Further details can be found in Table 2 and Fig. 2. Figure 2 MRI Imaging of Acute Microvascular Thrombosis in iTTP. Table 2 Laboratory test information of TTP patients No. PLT(×10^9/L) D-Dimer(ug/ml) ADAMTS13 activity(%) ADATS13 inhibitor titer total bilirubin(umol/l) Direct bil(umol/l)irubin Direct bilirubin(umol/l) LDH(IU/L) 1 6.0 1.26 <5 - 42.03 12.20 29.83 1305 2 17.0 2.16 <1 2.62 54.68 14.77 39.91 2299 3 5.0 3.52 <1 1.28 67.32 15.91 51.41 1142 4 5.0 0.69 <1 1.25 65 20.3 44.7 886 5 13.0 17.23 <1 1.43 73.16 15.31 57.85 1982 6 7.0 5.42 0 <0.6 49.35 12.19 37.16 1117 1.4 Diagnosis and Prognosis Referring to the 2022 edition of the Chinese Guidelines for the Diagnosis and Treatment of Thrombotic Thrombocytopenic Purpura 3 , all patients underwent ADAMTS13 activity testing, and all exhibited severe deficiency (< 10%). Additionally, five patients underwent ADAMTS13 inhibitor tests, and the results were positive. One report of the ADAMTS13 gene testing revealed the presence of five variants, among which four were synonymous variants, while the c.1342C > G (p.Q448E) mutation on exon 12 was a missense mutation. This mutation is a modifying variant that can modulate the activity of other pathogenic variants 4 , as detailed in Fig. 3. Figure 3 The missense mutation c.1342C>G (p.Q448E) on exon 12 of the patient's Exon12 exon. Given the low incidence and rapid development of iTTP, coupled with non-specific clinical, laboratory, and imaging manifestations, and the potential lack of clinician awareness, some patients experienced delays in ADAMTS13 activity and inhibitor testing, leading to a slow return of results. Consequently, the rate of misdiagnosis and underdiagnosis was notably high in this patient cohort. Out of the 6 cases, 2 patients (2/6) were misdiagnosed. One case (1/6) was misdiagnosed as acute infection, while the other case was misdiagnosed as acute coronary syndrome. This underscores the challenges in promptly identifying iTTP due to its varied and nonspecific presentation. All patients underwent TPE as part of their treatment. Among them, 3 cases received regular merovar treatment. Unfortunately, one patient succumbed after the initial merovar treatment, reflecting disease progression and challenges in maintaining vital signs.Treatment efficacy was assessed following the recently revised definition of iTTP treatment outcomes by the International TTP Working Group 5 . Three patients achieved complete remission, while the other three patients passed away in March 2021, July 2022, and March 2023, respectively. The PLASMIC-S scoring system, known for its rapid and accurate prediction of ADAMTS13 activity, holds significant clinical value in the early diagnosis and treatment of TTP 6 . In our cases, 5 out of 6 patients were classified in the high-risk group, with PLASMIC scores ranging from 6 to 7. This included 2 patients with a score of 7 and 3 patients with a score of 6. Notably, 1 patient initially classified in the intermediate-risk group with a score of 5 was later found to be in the high-risk group. This underscores the importance of PLASMIC-S in risk assessment and its potential impact on treatment decisions. Discussion In clinical practice, the primary physician must possess a comprehensive understanding of the clinical manifestations of TTP and demonstrate the ability to swiftly and accurately diagnose emergency situations, facilitating timely intervention and treatment guidance. Key clinical symptoms of TTP encompass fever, neurological manifestations, renal damage, anemia, thrombocytopenia, and various non-specific manifestations like malaise, abdominal pain, nausea, and occasional vomiting—often challenging to identify during initial diagnosis. Although moderate fever is infrequent at diagnosis, neurological signs, such as headache, convulsions, transient ischemic attacks (mild hemiparesis, aphasia, dysarthria, black haze), confusion, and coma, are crucial diagnostic indicators, present in 60% of patients. Due to the transient nature of these neurologic symptoms, often overlooked by both patients and clinicians, a thorough and systematic history is imperative. Renal involvement is uncommon (approximately 18% of cases) and typically manifests with moderately elevated serum creatinine below 200 µmol/L 7 . Thrombocytopenia below 20×10 9 /L is considered a poor prognostic factor 7 . Anemia commonly presents as normocytic normochromic hemolytic anemia with elevated indirect bilirubin, lactate dehydrogenase, decreased conjugated bead proteins, and a negative Coombs test. The diagnosis crucially relies on identifying finely fragmented erythrocytes on blood smear examination in the presence of reduced nucleated cells. However, fragmented red blood cells may vanish within the first 24 to 48 hours of the disease course, emphasizing the importance of early bone marrow aspiration and peripheral blood smears to prevent the omission of relevant supporting evidence 8 . For the challenging differentiation of iTTP and cTTP with atypical clinical symptoms in the early stages, commonly utilized methods involve assessing ADAMTS13 activity and autoantibodies. iTTP is diagnosed in the presence of anti-ADAMTS13 autoantibodies, while cTTP is suspected when ADAMTS13 activity is significantly reduced to < 10%, and anti-ADAMTS13 autoantibodies are negative. In cases of suspected cTTP, evaluating ADAMTS13 activity in both parents and children and performing ADAMTS13 genetic analysis is essential for accurate diagnosis 9 . A patient experienced a rash and fever a month after receiving the COVID-19 vaccine, preceding the initial signs of TTP by one week. There is evidence suggesting that the vaccine or its adjuvant components can generate autoantibodies, leading to cross-reactivity, potentially accelerating the development of autoimmune diseases 10 . While the COVID-19 vaccine's role in expediting TTP development cannot be ruled out in this patient, subsequent ADAMTS13 gene testing revealed the presence of five variants. Among these, c.1342C > G (p.Q448E) on exon 12 was identified as a missense mutation, acting as a modifying variant that influences the activity of other pathologic variants 4 . Details of specific gene alterations are provided in Fig. 2.The patient's daughter also exhibited abnormal immune system stimulation after receiving the COVID-19 vaccine 11 , which may accelerate TTP development in this patient 12 . Additionally, a missense mutation of c.2708C>T (p.S903L) was detected in the exon 21 of the daughter, initially not causing disease after the first vaccination. However, the possibility remains that revaccination with the COVID-19 vaccine may increase the genetic susceptibility in TTP, contributing to disease development. Consequently, a thorough medical history before COVID-19 vaccination is crucial, and careful clinical monitoring post-vaccination is advisable for patients with autoimmune diseases or suspected autoimmune predispositions in clinical or family histories. Nevertheless, clinical data on refractory and recurrent TTP cases are lacking, and further studies rely on observation, follow-up, refinement of clinical profiles, and expansion of sample sizes 12 . Other distinctions arise from the challenge that TTP often presents alongside other thrombotic microangiopathies during the initial acute phase, intensifying the complexity of distinguishing its clinical manifestations. The differentiation from hemolytic uremic syndrome primarily relies on identifying renal involvement and frequent infections, particularly with Shiga toxin-producing Escherichia coli O157:H7. However, the efficacy of plasma exchange in patients with hemolytic uremic syndrome is notably poor. Moreover, a rare thrombotic pseudomicroangiopathy linked to vitamin B12 deficiency has been documented in certain cases 11 . In contrast, megaloblastic anemia associated with vitamin B12 deficiency, diagnosed through bone marrow aspiration smear examination, can often be effectively corrected by vitamin B12 supplementation. Secondly, the differential diagnosis must discern the etiology of TTP as either autoimmune or secondary 13 . Especially during lupus flares, LPS, or scleroderma, the confluence of TTP can complicate autoimmune diseases. Additionally, pregnancy serves as a risk factor for acute TTP flares, with many women receiving a TTP diagnosis in adulthood after their initial flare during pregnancy. Women with TTP are often advised against risking pregnancy due to the potential for disease recurrence. Despite the ongoing efforts to understand and treat pregnancy complications in TTP, contemporary clinicians can provide a range of treatment strategies for women with TTP. Collaboration among healthcare professionals, particularly obstetricians specializing in high-risk pregnancies, has the potential to improve pregnancy outcomes. Recent data indicates a 100% live birth rate (15/15 live births) for cTTP patients in treated pregnancies and a 75% live birth rate for iTTP patients 12 . The mortality rate for TTP is initially high, reaching up to 90%, yet it has been significantly reduced to less than 10% through TPE 14 . The mechanism involves TPE not only replenishing plasma ADAMTS13 activity and eliminating anti-ADAMTS13 autoantibodies but also removing abnormal oversized relative molecular mass von Willebrand factor (vWF) multimers 15 .Some studies indicate that the timing of plasma exchange within 8 hours or 24 hours after disease diagnosis does not significantly affect the risk of patient death, whereas a delay of more than 24 hours in plasma exchange is linked to a notable increase in mortality and major thrombotic events 16 . Matsumoto et al 9 have concluded that delayed plasma exchange independently contributes to therapeutic failure. Therefore, in the clinical practice for all patients with iTTP after diagnosis, TPE should be initiated as early as possible. Various plasma types, including cryo-supernatant plasma, fresh frozen plasma, and solvent/detergent-treated plasma, can be utilized for TPE, potentially demonstrating comparable efficacy. Protocols vary, encompassing decisions on whether to taper or discontinue plasma therapy upon the return of platelet counts to normal, the volume of plasma replaced (1, 1.5, or 2 plasma volumes), and the frequency of plasma replacement (once or twice daily).Some scholars suggest that the number of TPE treatments may not significantly impact patient prognosis, and the selection can be based on the clinical manifestations and laboratory results of patients. Patients with persistent unremitting symptoms and abnormal laboratory tests may benefit from more frequent plasma exchange to achieve early remission. The recommended daily TPE plasma volume is 60 mL/kg (1.5 plasma volumes), administered 1–2 times/day, initiated within 6 hours after diagnosis, until the platelet count surpasses 150×10 9 /L for 48 hours, and the lactate dehydrogenase (LDH) is less than 1.5 times the upper limit of normal 17 , 18 . Unfortunately, regional and technological limitations, as well as economic conditions, often lead to delayed application of TPE. Some studies suggest that fresh frozen plasma (FFP), solvent/detergent fresh frozen plasma (SD-FFP), and cryosupernatant plasma (CP) contain equivalent ADAMTS13 activity 19 . While FFP can serve as a universally accepted method for the prevention and treatment of early TTP, the usual dose is 15 mL/kg body weight every 3–5 days or once a week 20 . In clinical practice, apart from TPE, patients with TTP may receive treatment with corticosteroids, immunosuppressive agents, and drugs inhibiting the collagen-von Willebrand factor (vWF)-platelet response axis. Current strategies frequently include escalating to twice-daily plasma exchange and utilizing rituximab or other immunosuppressive therapies. Ongoing advancements in adjuvant and disease-modifying therapies provide novel treatment possibilities. Rituximab, a monoclonal antibody targeting the CD20 antigen on B lymphocytes, is presently employed in treating B-cell tumor formation and autoimmune diseases.Literature reports 21 suggest that rituximab can be employed in patients with relapsed/refractory TTP. It works by eliminating circulating B lymphocytes, reducing the production of anti-ADAMTS13 autoantibodies. The use of rituximab alone in treating refractory/relapsed TTP has resulted in remission in 87%-100% of patients, according to Cuker 22 . He also suggests that integrating rituximab with plasma exchange and hormonal therapy reduces the risk of TTP recurrence. iTTP often presents as the first manifestation of progressive primary disease. However, in 30% of cases 21 , its evolution is characterized by alternating periods of relapse and remission, which is referred to as chronic relapse or recurrent TTP. iTTP relapse has historically been a persistent therapeutic challenge, with 20–50% of patients relapsing after recovery from an acute episode 22 . Recurrence is currently difficult to predict and often occurs in the first year of illness or even later. Regular monitoring helps to better follow up patients with TTP. In addition to routine platelet monitoring, measurement of ADAMTS13 activity and autoantibodies are important components of surveillance 23 . The number of patients with recurrent TTP in our case was 0. Regular follow-up and monitoring is awaited, especially in the era of continuous updating of new drugs, making the challenge of preventing recurrent, refractory TTP even more important. Of the three patients with TTP who were treated with rituximab, one patient died without response to treatment, and two patients went into remission and have not relapsed since then. Patients diagnosed with TTP may encounter lasting effects, including stroke, heart attack, kidney failure, and neurocognitive issues such as persistent memory and attention problems, mild cognitive abnormalities, and depression. Regular monitoring at the Oklahoma Health Sciences Center has revealed a notably higher incidence of cognitive abnormalities and depression among TTP patients when compared to the general U.S. population 24 . Cognitive function, encompassing complex attention, concentration skills, information processing speed, and rapid speech production, is increasingly recognized as a crucial endpoint in clinical trials. Additional research into cognitive dysfunction and depressive status in TTP patients is warranted, with routine assessments of cognitive difficulties recommended post-recovery from acute episodes.Clinically, in addition to TPE, patients with TTP may be treated with corticosteroids, immunosuppressants, and drugs that inhibit the collagen-vWF-platelet response axis 24 . Ofatumumab and Otolizumab, fully humanized second-generation anti-CD20 antibodies, have proven effective and safe in iTTP patients intolerant to rituximab due to adverse events such as hypersensitivity reactions. Recently, a novel immunosuppressive drug, Caplacizumab, was introduced. It is a humanized single-variable domain immunoglobulin fragment specifically targeting the A1 structural domain of VWF, blocking its interaction with the platelet GP1b-IX-V receptor 25 . This VWF nanobody inhibits platelet binding to VWF, preventing microthrombosis. Caplacizumab has demonstrated improved outcomes in iTTP when used in combination with standard therapy, offering an attractive new therapeutic option for acquired TTP in clinical settings 25 . However, this drug is expensive and has a relatively low availability rate 26 .According to our experience, due to the lower economic level and relatively small population, availability is even lower in the northeastern region of the country. Multiple trials have confirmed the integration of quadruple therapy—comprising TPE, glucocorticoids, rituximab, and Caplacizumab—into the standard of care for immune TTP across several Western countries 27 . While there has been notable improvement in overall survival for acute exacerbations of iTTP, inherent risks associated with TPE persist, encompassing allergic reactions, catheter-related complications, and volume overload, particularly in the context of plasma infusion. In contrast, the innovative recombinant ADAMTS13-targeted therapy demonstrates potential for alleviating severe TTP symptoms and reducing the frequency of required TPE sessions in the treatment of iTTP 28 . Targeted therapy with ADAMTS-13 offers an avenue to address the root cause of TTP, eliminating dependence on plasma therapy conditions 29 . This holds significant promise for the future treatment of iTTP, expanding decision-making options for patients in China facing refractory relapses. To summarize the cases, the potential reasons for the misdiagnosis of these patients include several factors. Patients presenting with thrombocytopenia or primary diseases as their initial manifestation in non-hematological departments often do not exhibit the typical "triad" or "pentad" symptoms at the time of diagnosis. This failure to recognize the disease early on leads to the progression of the disease into advanced stages, resulting in delayed plasma exchange. Furthermore, during the course of disease treatment, some patients may either automatically discontinue treatment or develop comorbidities such as pulmonary infection or cerebral hemorrhage, further contributing to poor outcomes. The plasmic score specifically includes platelet count 2.5% or haptoglobin below the lower limit of detection or indirect bilirubin > 2.0mg/dl), no active cancer, no history of solid organ or stem cell transplantation, mean corpuscular volume (MCV) < 90fL, prothrombin time-international normalized ratio (PT-INR) < 1.5, and creatinine < 2.0mg/dl. Among them, 5 points are moderate risk, while 6–7 points are highly predictive of TTP. This has certain clinical guiding for early diagnosis, intervention, and prognosis. In the pursuit of enhancing patient prognosis and outcomes, numerous challenges and complications associated with TTP treatment demand attention. Patients experiencing relapsed or refractory TTP exhibit slow and incomplete responses to standard TPE. While TPE, coupled with improved immunosuppressive and immunomodulatory therapies, has positively influenced patient prognosis, the mortality rate for TTP persists at 10–20%, rising even higher in refractory cases 30 .Current clinical strategies involve intensifying treatment through twice-daily plasma exchange and incorporating rituximab or other immunosuppressive therapies. Although these therapeutic advancements have positively impacted TTP outcomes, early diagnosis and prompt initiation of appropriate therapy remain crucial to achieving optimal results. TPE stands as the standard of care for iTTP, with its efficacy validated in randomized controlled trials 31 . As new drugs are continually introduced, and clinical data is updated, therapeutic plasma exchange and hormone-based diagnostic and treatment programs are refined. This ongoing improvement is anticipated to offer a broader array of choices and options, fostering multidisciplinary and comprehensive diagnostic and treatment strategies for iTTP in the future. Declarations Acknowledgements Approval was obtained from the Institutional Research Board of The Second Hospital of Jilin University. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Author Contributions Statement The authors affirm that all data were internally generated, and no paper mill was utilized. WLY is the first auther and LJL is the corresponding author.RLS and TL collected the data.WLY,LJL and SWZ conceptualized and designed the experiments, analyzed the data.WLY,SWZ and RLS prepared figures 1-3. All authors contributed to the writing of the paper, provided editorial input, and approved the final draft. Funding We sincerely appreciate the financial support provided by the Natural Science Foundation of Jilin Province through the Jilin Science and Technology Development Program Project(YDZJ202301ZYTS065). Additionally, we acknowledge the invaluable assistance received from the Department of Oncology and Hematology and the Department of Critical Care Medicine at the Second Hospital of Jilin University for their contributions to this study. Data Availablility The author confirms that all data are included in this published article. Furthermore, sources and data supporting the findings of this study were all publicly available at the time of submission. Ethics approval Approval was obtained from the Institutional Research Board of The Second Hospital of Jilin University. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Conflict of interest The authors declare no competing interests. References Elizabeth MS, Wenjing C, Huy PP, et al. 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Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol . Aug 2012;158(3):323-35. doi:10.1111/j.1365-2141.2012.09167.x Sadler JE. Pathophysiology of thrombotic thrombocytopenic purpura. Blood . 2017;130(10):1181-1188. doi:10.1182/blood-2017-04-636431 Asmis LM, Serra A, Krafft A, et al. Recombinant ADAMTS13 for Hereditary Thrombotic Thrombocytopenic Purpura. N Engl J Med . Dec 22 2022;387(25):2356-2361. doi:10.1056/NEJMoa2211113 Sadler JE, Moake JL, Miyata T, George JN. Recent advances in thrombotic thrombocytopenic purpura. Hematology Am Soc Hematol Educ Program . 2004:407-23. doi:10.1182/asheducation-2004.1.407 Hovinga JAK, Vesely SK, Terrell DR, Lämmle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood . 2010/02/25/ 2010;115(8):1500-1511. doi:https://doi.org/10.1182/blood-2009-09-243790 Schleinitz N, Ebbo M, Mazodier K, et al. Rituximab as preventive therapy of a clinical relapse in TTP with ADAMTS13 inhibitor. Am J Hematol . May 2007;82(5):417-8. doi:10.1002/ajh.20764 Deford CC, Reese JA, Schwartz LH, et al. Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura. Blood . Sep 19 2013;122(12):2023-9; quiz 2142. doi:10.1182/blood-2013-04-496752 Callewaert F, Roodt J, Ulrichts H, et al. Evaluation of efficacy and safety of the anti-VWF Nanobody ALX-0681 in a preclinical baboon model of acquired thrombotic thrombocytopenic purpura. Blood . Oct 25 2012;120(17):3603-10. doi:10.1182/blood-2012-04-420943 Tse B, Buchholz M, Pavenski K. Management of immune thrombotic thrombocytopenic purpura with caplacizumab: a Canadian, single-centre, real-world experience. Platelets . Dec 2023;34(1)2157807. doi:10.1080/09537104.2022.2157807 Zheng L, Zheng XL. How should caplacizumab be used for treatment of immune thrombotic thrombocytopenic purpura? Ann Blood . Jun 30 2023;8doi:10.21037/aob-21-87 Tersteeg C, Schiviz A, De Meyer SF, et al. Potential for Recombinant ADAMTS13 as an Effective Therapy for Acquired Thrombotic Thrombocytopenic Purpura. Arteriosclerosis Thrombosis and Vascular Biology . Nov 2015;35(11):2336-2342. doi:10.1161/atvbaha.115.306014 Moroniti JJ, Vrbensky JR, Nazy I, Arnold DM. Targeted ADAMTS-13 replacement therapy for thrombotic thrombocytopenic purpura. J Thromb Haemost . Dec 22 2023;doi:10.1016/j.jtha.2023.11.030 Verbeke L, Delforge M, Dierickx D. Current insight into thrombotic thrombocytopenic purpura. Blood Coagul Fibrinolysis . Jan 2010;21(1):3-10. doi:10.1097/MBC.0b013e32833335eb Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med . Aug 8 1991;325(6):393-7. doi:10.1056/nejm199108083250604 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4464305","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":308360186,"identity":"e99ba679-f869-42ef-ab69-6508fe9b47d6","order_by":0,"name":"Wang Lingyu","email":"","orcid":"","institution":"the Second Affiliated Hospital of Jilin University","correspondingAuthor":false,"prefix":"","firstName":"Wang","middleName":"","lastName":"Lingyu","suffix":""},{"id":308360187,"identity":"6c77a5a8-c6f5-4289-a37b-8ed6f5c0a565","order_by":1,"name":"Shen Weizhang","email":"","orcid":"","institution":"the Second Affiliated Hospital of Jilin University","correspondingAuthor":false,"prefix":"","firstName":"Shen","middleName":"","lastName":"Weizhang","suffix":""},{"id":308360188,"identity":"af65e5ca-5792-429b-a084-62fb3f6ab8da","order_by":2,"name":"Ren Lishen","email":"","orcid":"","institution":"the Second Affiliated Hospital of Jilin University","correspondingAuthor":false,"prefix":"","firstName":"Ren","middleName":"","lastName":"Lishen","suffix":""},{"id":308360190,"identity":"232fa21c-b15d-4eec-923a-78c596644540","order_by":3,"name":"Tan Lei","email":"","orcid":"","institution":"the Second Affiliated Hospital of Jilin University","correspondingAuthor":false,"prefix":"","firstName":"Tan","middleName":"","lastName":"Lei","suffix":""},{"id":308360192,"identity":"1375f3c3-70b1-43a8-bbdf-2fa9a8baa96c","order_by":4,"name":"Li Jinliang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIiWNgGAWjYBACAzBZwCbDxt588MEHAxs7IrUYsPHw8RxLNpxRkJZMrBYGHjmJHDNpng+HGBsIaTFnP3vsMY8BHw8bSIuNwQFmBvbDRzfg02LZk5duzAN0GBvPs2LrHIM7fAw8aWk38DrsAMg9IC3syRtv5xg8Y2aQ4DHDr+X8G6gWhgQDaQuDw4wNBLXcgNnCkWIkzUCclnfphnPAfgEGco9BWjIbQb+czz324E3FMTn5dmBU/vhjY8fPfvgYXi0MDDxsTDwMxxB8NvzKIVoYfzDUEFY3CkbBKBgFIxcAAJQJQ/vuD0KpAAAAAElFTkSuQmCC","orcid":"","institution":"the Second Affiliated Hospital of Jilin University","correspondingAuthor":true,"prefix":"","firstName":"Li","middleName":"","lastName":"Jinliang","suffix":""}],"badges":[],"createdAt":"2024-05-23 05:14:19","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-4464305/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4464305/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57955322,"identity":"28189450-f92a-419b-bea2-43d817f670ee","added_by":"auto","created_at":"2024-06-07 23:25:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":426425,"visible":true,"origin":"","legend":"\u003cp\u003eFragmented Erythrocytes in Peripheral Blood Smears of iTTP Patients\u003c/p\u003e\n\u003cp\u003eRed arrow indicated the schistocytes.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4464305/v1/41c42ccd4679dbf290838307.png"},{"id":57954737,"identity":"9bb03cd0-6d24-453a-abab-3e09c00b845a","added_by":"auto","created_at":"2024-06-07 23:17:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":308697,"visible":true,"origin":"","legend":"\u003cp\u003eMRI Imaging of Acute Microvascular Thrombosis in iTTP.\u003c/p\u003e\n\u003cp\u003eA：ADC;B:DWI;White arrow indicated the abnormal signal shadow\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4464305/v1/7db6feb862bf4486928cdd64.png"},{"id":57954739,"identity":"62023c7d-ad12-49ce-9044-f7f3ba23c004","added_by":"auto","created_at":"2024-06-07 23:17:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":173051,"visible":true,"origin":"","legend":"\u003cp\u003eThe missense mutation c.1342C＞G (p.Q448E) on exon 12 of the patient's Exon12 exon.\u003c/p\u003e\n\u003cp\u003eBlack arrow indicated the missense mutation of the patient’s genes.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4464305/v1/82d256e775a4089a6cf7dd2d.png"},{"id":61275883,"identity":"6240597b-1ae8-4242-bc5d-4fd6b82162ad","added_by":"auto","created_at":"2024-07-29 03:40:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1298295,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4464305/v1/2f4e8e2a-a06a-4801-af19-a3a14544a25c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Analysis of clinical factors in first diagnosis of immune thrombotic thrombocytopenic purpura with report of 6 cases","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThrombotic thrombocytopenic purpura (TTP) is a rare and serious hematologic disorder, typically occurring at an incidence of approximately\u0026nbsp;2-6\u0026nbsp;cases per million people\u003csup\u003e1\u003c/sup\u003e. The classical clinical manifestations of TTP encompass microangiopathic hemolysis, thrombocytopenia, neurologic symptoms, fever, and renal damage, collectively forming the Pentalogy. Some patients may exhibit only the initial three symptoms, recognized as trichotillomania. Hereditary TTP, also known as congenital thrombotic thrombocytopenic purpura (cTTP), results from a severe deficiency of plasma ADAMTS5\u0026nbsp;activity due to mutations in ADAMTS13. In contrast, iTTP, triggered by immune-mediated autoantibodies inhibiting plasma ADAMTS6\u0026nbsp;activity, is characterized by low platelet counts, anemia, and microvascular thrombosis.\u003c/p\u003e\n\u003cp\u003eThe underlying mechanism in TTP involves excessive platelet aggregation in multiple organs, leading to the accumulation of unfolded, high-molecular-weight vascular hemophilic factor multimers in plasma, causing a significant increase in shear stress. The resulting inability to process these multimers into smaller, less adhesive forms is associated with ADAMTS13\u0026nbsp;dysfunction. ADAMTS1\u0026nbsp;deficiency may stem from mutations in the encoding gene or acquired autoantibodies, influencing enzyme function through direct neutralization or a conditioning process involving immune complex formation with ADAMTS2, subsequently cleared by phagocytes\u0026nbsp;\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eStudies indicate that\u0026nbsp;33%-90% of TTP patients exhibit severe ADAMTS13\u0026nbsp;deficiency, while ADAMTS4\u0026nbsp;activity is typically normal or only slightly reduced in patients with other causes of thrombocytopenia\u0026nbsp;\u003csup\u003e2\u003c/sup\u003e. In this report, we present clinical data from six iTTP patients treated at the Second Hospital of Jilin University between January 2020 and April 2023. Our analysis, in conjunction with existing literature, explores their clinical manifestations, laboratory and imaging characteristics, pathological features, diagnosis, and treatment. By discussing clinicopathological features and prognostic factors, we aim to enhance the understanding of TTP and contribute to the broader knowledge of this disease.\u003c/p\u003e"},{"header":"Information and Methods","content":"\u003cdiv id=\"Sec2\"\u003e\n \u003ch2\u003e1.1 General Information\u003c/h2\u003e\n \u003cp\u003eThe retrospective analysis involved the clinical data of six patients diagnosed with TTP who sought medical care at the Second Hospital of Jilin University between January 2020 and April 2023. The cohort comprised 5 males (83.33%) and 1 female (16.67%), with ages ranging from 29 to 84 years and a median age of 58 years. Descriptive analysis was applied to all cases, and confirmation of diagnosis was based on laboratory examination, peripheral blood smear, and ADAMTS13 testing. Retrospective analysis encompassed gender, age, clinical manifestations, accompanying symptoms, laboratory and imaging test results, treatment modalities, and prognosis for each patient.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec3\"\u003e\n \u003ch2\u003e1.2 Clinical Manifestations\u003c/h2\u003e\n \u003cp\u003eAll six patients exhibited common features, including thrombocytopenia, microangiopathic hemolytic anemia, and neuropsychiatric symptoms. Specifically, 4 cases (66.67%) manifested renal function impairment, while 2 cases (33.33%) presented with fever. Among the cases, 2 showed the typical \u0026quot;pentad\u0026quot; manifestations, 2 displayed \u0026quot;quadruple\u0026quot; manifestations, and 2 presented with \u0026quot;triple\u0026quot; manifestations. Further details can be found in Table \u003cspan\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eClinical information of TTP patients\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"9\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo.\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTime of onset\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMAHA\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNeurological abnormalities\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eImpaired kidney function\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2021-03-27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2023-03-07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2022-06-07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2022-07-12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2023-02-15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2021-07-09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003eNotes: M:male; F:female;Y:yes;N:no\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\"\u003e\n \u003ch2\u003e1.3 Laboratory, Imaging, and Other Examinations\u003c/h2\u003e\n \u003cp\u003eAll 6 patients underwent peripheral blood smear examinations, with each smear counting 1,000 erythrocytes. The results revealed varying numbers of broken erythrocytes, indicating different degrees of heterogeneous erythrocytosis. This phenomenon is primarily attributed to the formation of broken erythrocytes and can be observed as tear drop-shaped cells, scattered lobes of erythrocytes, among other manifestations.Typical peripheral blood smears exhibited the presence of broken red blood cells, as highlighted by the arrows in Fig.\u0026nbsp;1.\u003c/p\u003e\n \u003cp\u003eRed arrow indicated the schistocytes.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFigure\u0026nbsp;1\u003c/strong\u003e Fragmented Erythrocytes in Peripheral Blood Smears of iTTP Patients\u003c/p\u003e\n \u003cp\u003eAll patients exhibited mild personality changes and neuropsychiatric symptoms. Among them, four cases presented imaging changes, with one case not undergoing head imaging. Among the patients who underwent head CT examination (n\u0026thinsp;=\u0026thinsp;3), multiple punctate, patchy, and blurred low-density shadows were observed. Two cases that underwent magnetic head examination showed new-onset speckled or patchy high signal, with the ADC map indicating low signal. These manifestations posed challenges in distinguishing them from lacunar cerebral infarction, and were considered to be associated with acute microvascular thrombosis, albeit lacking diagnostic specificity. Further details can be found in Table \u003cspan\u003e2\u003c/span\u003e and Fig. 2.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFigure\u0026nbsp;2\u003c/strong\u003e MRI Imaging of Acute Microvascular Thrombosis in iTTP.\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 2\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eLaboratory test information of TTP patients\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"9\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo.\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePLT(\u0026times;10^9/L)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eD-Dimer(ug/ml)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eADAMTS13 activity(%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eADATS13 inhibitor titer\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003etotal bilirubin(umol/l)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDirect bil(umol/l)irubin\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDirect bilirubin(umol/l)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLDH(IU/L)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1305\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e39.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2299\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e51.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1142\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e886\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e57.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1982\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1117\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\"\u003e\n \u003ch2\u003e1.4 Diagnosis and Prognosis\u003c/h2\u003e\n \u003cp\u003eReferring to the 2022 edition of the Chinese Guidelines for the Diagnosis and Treatment of Thrombotic Thrombocytopenic Purpura \u003csup\u003e\u003cspan\u003e3\u003c/span\u003e\u003c/sup\u003e, all patients underwent ADAMTS13 activity testing, and all exhibited severe deficiency (\u0026lt;\u0026thinsp;10%). Additionally, five patients underwent ADAMTS13 inhibitor tests, and the results were positive. One report of the ADAMTS13 gene testing revealed the presence of five variants, among which four were synonymous variants, while the c.1342C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Q448E) mutation on exon 12 was a missense mutation. This mutation is a modifying variant that can modulate the activity of other pathogenic variants \u003csup\u003e\u003cspan\u003e4\u003c/span\u003e\u003c/sup\u003e, as detailed in Fig.\u0026nbsp;3.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFigure\u0026nbsp;3\u003c/strong\u003e The missense mutation c.1342C\u0026gt;G (p.Q448E) on exon 12 of the patient\u0026apos;s Exon12 exon.\u003c/p\u003e\n \u003cp\u003eGiven the low incidence and rapid development of iTTP, coupled with non-specific clinical, laboratory, and imaging manifestations, and the potential lack of clinician awareness, some patients experienced delays in ADAMTS13 activity and inhibitor testing, leading to a slow return of results. Consequently, the rate of misdiagnosis and underdiagnosis was notably high in this patient cohort. Out of the 6 cases, 2 patients (2/6) were misdiagnosed. One case (1/6) was misdiagnosed as acute infection, while the other case was misdiagnosed as acute coronary syndrome. This underscores the challenges in promptly identifying iTTP due to its varied and nonspecific presentation.\u003c/p\u003e\n \u003cp\u003eAll patients underwent TPE as part of their treatment. Among them, 3 cases received regular merovar treatment. Unfortunately, one patient succumbed after the initial merovar treatment, reflecting disease progression and challenges in maintaining vital signs.Treatment efficacy was assessed following the recently revised definition of iTTP treatment outcomes by the International TTP Working Group \u003csup\u003e\u003cspan\u003e5\u003c/span\u003e\u003c/sup\u003e. Three patients achieved complete remission, while the other three patients passed away in March 2021, July 2022, and March 2023, respectively.\u003c/p\u003e\n \u003cp\u003eThe PLASMIC-S scoring system, known for its rapid and accurate prediction of ADAMTS13 activity, holds significant clinical value in the early diagnosis and treatment of TTP \u003csup\u003e\u003cspan\u003e6\u003c/span\u003e\u003c/sup\u003e. In our cases, 5 out of 6 patients were classified in the high-risk group, with PLASMIC scores ranging from 6 to 7. This included 2 patients with a score of 7 and 3 patients with a score of 6. Notably, 1 patient initially classified in the intermediate-risk group with a score of 5 was later found to be in the high-risk group. This underscores the importance of PLASMIC-S in risk assessment and its potential impact on treatment decisions.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn clinical practice, the primary physician must possess a comprehensive understanding of the clinical manifestations of TTP and demonstrate the ability to swiftly and accurately diagnose emergency situations, facilitating timely intervention and treatment guidance. Key clinical symptoms of TTP encompass fever, neurological manifestations, renal damage, anemia, thrombocytopenia, and various non-specific manifestations like malaise, abdominal pain, nausea, and occasional vomiting\u0026mdash;often challenging to identify during initial diagnosis. Although moderate fever is infrequent at diagnosis, neurological signs, such as headache, convulsions, transient ischemic attacks (mild hemiparesis, aphasia, dysarthria, black haze), confusion, and coma, are crucial diagnostic indicators, present in 60% of patients. Due to the transient nature of these neurologic symptoms, often overlooked by both patients and clinicians, a thorough and systematic history is imperative.\u003c/p\u003e \u003cp\u003eRenal involvement is uncommon (approximately 18% of cases) and typically manifests with moderately elevated serum creatinine below 200 \u0026micro;mol/L \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Thrombocytopenia below 20\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L is considered a poor prognostic factor \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Anemia commonly presents as normocytic normochromic hemolytic anemia with elevated indirect bilirubin, lactate dehydrogenase, decreased conjugated bead proteins, and a negative Coombs test. The diagnosis crucially relies on identifying finely fragmented erythrocytes on blood smear examination in the presence of reduced nucleated cells. However, fragmented red blood cells may vanish within the first 24 to 48 hours of the disease course, emphasizing the importance of early bone marrow aspiration and peripheral blood smears to prevent the omission of relevant supporting evidence \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFor the challenging differentiation of iTTP and cTTP with atypical clinical symptoms in the early stages, commonly utilized methods involve assessing ADAMTS13 activity and autoantibodies. iTTP is diagnosed in the presence of anti-ADAMTS13 autoantibodies, while cTTP is suspected when ADAMTS13 activity is significantly reduced to \u0026lt;\u0026thinsp;10%, and anti-ADAMTS13 autoantibodies are negative. In cases of suspected cTTP, evaluating ADAMTS13 activity in both parents and children and performing ADAMTS13 genetic analysis is essential for accurate diagnosis \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eA patient experienced a rash and fever a month after receiving the COVID-19 vaccine, preceding the initial signs of TTP by one week. There is evidence suggesting that the vaccine or its adjuvant components can generate autoantibodies, leading to cross-reactivity, potentially accelerating the development of autoimmune diseases \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. While the COVID-19 vaccine's role in expediting TTP development cannot be ruled out in this patient, subsequent ADAMTS13 gene testing revealed the presence of five variants. Among these, c.1342C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Q448E) on exon 12 was identified as a missense mutation, acting as a modifying variant that influences the activity of other pathologic variants \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Details of specific gene alterations are provided in Fig.\u0026nbsp;2.The patient's daughter also exhibited abnormal immune system stimulation after receiving the COVID-19 vaccine \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, which may accelerate TTP development in this patient \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Additionally, a missense mutation of c.2708C\u0026gt;T (p.S903L) was detected in the exon 21 of the daughter, initially not causing disease after the first vaccination. However, the possibility remains that revaccination with the COVID-19 vaccine may increase the genetic susceptibility in TTP, contributing to disease development. Consequently, a thorough medical history before COVID-19 vaccination is crucial, and careful clinical monitoring post-vaccination is advisable for patients with autoimmune diseases or suspected autoimmune predispositions in clinical or family histories. Nevertheless, clinical data on refractory and recurrent TTP cases are lacking, and further studies rely on observation, follow-up, refinement of clinical profiles, and expansion of sample sizes \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOther distinctions arise from the challenge that TTP often presents alongside other thrombotic microangiopathies during the initial acute phase, intensifying the complexity of distinguishing its clinical manifestations. The differentiation from hemolytic uremic syndrome primarily relies on identifying renal involvement and frequent infections, particularly with Shiga toxin-producing Escherichia coli O157:H7. However, the efficacy of plasma exchange in patients with hemolytic uremic syndrome is notably poor. Moreover, a rare thrombotic pseudomicroangiopathy linked to vitamin B12 deficiency has been documented in certain cases \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. In contrast, megaloblastic anemia associated with vitamin B12 deficiency, diagnosed through bone marrow aspiration smear examination, can often be effectively corrected by vitamin B12 supplementation.\u003c/p\u003e \u003cp\u003eSecondly, the differential diagnosis must discern the etiology of TTP as either autoimmune or secondary \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Especially during lupus flares, LPS, or scleroderma, the confluence of TTP can complicate autoimmune diseases. Additionally, pregnancy serves as a risk factor for acute TTP flares, with many women receiving a TTP diagnosis in adulthood after their initial flare during pregnancy. Women with TTP are often advised against risking pregnancy due to the potential for disease recurrence. Despite the ongoing efforts to understand and treat pregnancy complications in TTP, contemporary clinicians can provide a range of treatment strategies for women with TTP. Collaboration among healthcare professionals, particularly obstetricians specializing in high-risk pregnancies, has the potential to improve pregnancy outcomes. Recent data indicates a 100% live birth rate (15/15 live births) for cTTP patients in treated pregnancies and a 75% live birth rate for iTTP patients \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe mortality rate for TTP is initially high, reaching up to 90%, yet it has been significantly reduced to less than 10% through TPE \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. The mechanism involves TPE not only replenishing plasma ADAMTS13 activity and eliminating anti-ADAMTS13 autoantibodies but also removing abnormal oversized relative molecular mass von Willebrand factor (vWF) multimers \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.Some studies indicate that the timing of plasma exchange within 8 hours or 24 hours after disease diagnosis does not significantly affect the risk of patient death, whereas a delay of more than 24 hours in plasma exchange is linked to a notable increase in mortality and major thrombotic events \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Matsumoto et al \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e have concluded that delayed plasma exchange independently contributes to therapeutic failure. Therefore, in the clinical practice for all patients with iTTP after diagnosis, TPE should be initiated as early as possible. Various plasma types, including cryo-supernatant plasma, fresh frozen plasma, and solvent/detergent-treated plasma, can be utilized for TPE, potentially demonstrating comparable efficacy. Protocols vary, encompassing decisions on whether to taper or discontinue plasma therapy upon the return of platelet counts to normal, the volume of plasma replaced (1, 1.5, or 2 plasma volumes), and the frequency of plasma replacement (once or twice daily).Some scholars suggest that the number of TPE treatments may not significantly impact patient prognosis, and the selection can be based on the clinical manifestations and laboratory results of patients. Patients with persistent unremitting symptoms and abnormal laboratory tests may benefit from more frequent plasma exchange to achieve early remission.\u003c/p\u003e \u003cp\u003eThe recommended daily TPE plasma volume is 60 mL/kg (1.5 plasma volumes), administered 1\u0026ndash;2 times/day, initiated within 6 hours after diagnosis, until the platelet count surpasses 150\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L for 48 hours, and the lactate dehydrogenase (LDH) is less than 1.5 times the upper limit of normal \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Unfortunately, regional and technological limitations, as well as economic conditions, often lead to delayed application of TPE. Some studies suggest that fresh frozen plasma (FFP), solvent/detergent fresh frozen plasma (SD-FFP), and cryosupernatant plasma (CP) contain equivalent ADAMTS13 activity \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. While FFP can serve as a universally accepted method for the prevention and treatment of early TTP, the usual dose is 15 mL/kg body weight every 3\u0026ndash;5 days or once a week \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn clinical practice, apart from TPE, patients with TTP may receive treatment with corticosteroids, immunosuppressive agents, and drugs inhibiting the collagen-von Willebrand factor (vWF)-platelet response axis. Current strategies frequently include escalating to twice-daily plasma exchange and utilizing rituximab or other immunosuppressive therapies. Ongoing advancements in adjuvant and disease-modifying therapies provide novel treatment possibilities. Rituximab, a monoclonal antibody targeting the CD20 antigen on B lymphocytes, is presently employed in treating B-cell tumor formation and autoimmune diseases.Literature reports \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e suggest that rituximab can be employed in patients with relapsed/refractory TTP. It works by eliminating circulating B lymphocytes, reducing the production of anti-ADAMTS13 autoantibodies. The use of rituximab alone in treating refractory/relapsed TTP has resulted in remission in 87%-100% of patients, according to Cuker \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. He also suggests that integrating rituximab with plasma exchange and hormonal therapy reduces the risk of TTP recurrence.\u003c/p\u003e \u003cp\u003eiTTP often presents as the first manifestation of progressive primary disease. However, in 30% of cases \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, its evolution is characterized by alternating periods of relapse and remission, which is referred to as chronic relapse or recurrent TTP. iTTP relapse has historically been a persistent therapeutic challenge, with 20\u0026ndash;50% of patients relapsing after recovery from an acute episode \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Recurrence is currently difficult to predict and often occurs in the first year of illness or even later. Regular monitoring helps to better follow up patients with TTP. In addition to routine platelet monitoring, measurement of ADAMTS13 activity and autoantibodies are important components of surveillance \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. The number of patients with recurrent TTP in our case was 0. Regular follow-up and monitoring is awaited, especially in the era of continuous updating of new drugs, making the challenge of preventing recurrent, refractory TTP even more important. Of the three patients with TTP who were treated with rituximab, one patient died without response to treatment, and two patients went into remission and have not relapsed since then.\u003c/p\u003e \u003cp\u003ePatients diagnosed with TTP may encounter lasting effects, including stroke, heart attack, kidney failure, and neurocognitive issues such as persistent memory and attention problems, mild cognitive abnormalities, and depression. Regular monitoring at the Oklahoma Health Sciences Center has revealed a notably higher incidence of cognitive abnormalities and depression among TTP patients when compared to the general U.S. population \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Cognitive function, encompassing complex attention, concentration skills, information processing speed, and rapid speech production, is increasingly recognized as a crucial endpoint in clinical trials. Additional research into cognitive dysfunction and depressive status in TTP patients is warranted, with routine assessments of cognitive difficulties recommended post-recovery from acute episodes.Clinically, in addition to TPE, patients with TTP may be treated with corticosteroids, immunosuppressants, and drugs that inhibit the collagen-vWF-platelet response axis \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOfatumumab and Otolizumab, fully humanized second-generation anti-CD20 antibodies, have proven effective and safe in iTTP patients intolerant to rituximab due to adverse events such as hypersensitivity reactions. Recently, a novel immunosuppressive drug, Caplacizumab, was introduced. It is a humanized single-variable domain immunoglobulin fragment specifically targeting the A1 structural domain of VWF, blocking its interaction with the platelet GP1b-IX-V receptor \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. This VWF nanobody inhibits platelet binding to VWF, preventing microthrombosis. Caplacizumab has demonstrated improved outcomes in iTTP when used in combination with standard therapy, offering an attractive new therapeutic option for acquired TTP in clinical settings \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. However, this drug is expensive and has a relatively low availability rate \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.According to our experience, due to the lower economic level and relatively small population, availability is even lower in the northeastern region of the country.\u003c/p\u003e \u003cp\u003eMultiple trials have confirmed the integration of quadruple therapy\u0026mdash;comprising TPE, glucocorticoids, rituximab, and Caplacizumab\u0026mdash;into the standard of care for immune TTP across several Western countries \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. While there has been notable improvement in overall survival for acute exacerbations of iTTP, inherent risks associated with TPE persist, encompassing allergic reactions, catheter-related complications, and volume overload, particularly in the context of plasma infusion. In contrast, the innovative recombinant ADAMTS13-targeted therapy demonstrates potential for alleviating severe TTP symptoms and reducing the frequency of required TPE sessions in the treatment of iTTP \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Targeted therapy with ADAMTS-13 offers an avenue to address the root cause of TTP, eliminating dependence on plasma therapy conditions \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. This holds significant promise for the future treatment of iTTP, expanding decision-making options for patients in China facing refractory relapses.\u003c/p\u003e \u003cp\u003eTo summarize the cases, the potential reasons for the misdiagnosis of these patients include several factors. Patients presenting with thrombocytopenia or primary diseases as their initial manifestation in non-hematological departments often do not exhibit the typical \"triad\" or \"pentad\" symptoms at the time of diagnosis. This failure to recognize the disease early on leads to the progression of the disease into advanced stages, resulting in delayed plasma exchange. Furthermore, during the course of disease treatment, some patients may either automatically discontinue treatment or develop comorbidities such as pulmonary infection or cerebral hemorrhage, further contributing to poor outcomes. The plasmic score specifically includes platelet count\u0026thinsp;\u0026lt;\u0026thinsp;30\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, hemolysis (reticulocyte count\u0026thinsp;\u0026gt;\u0026thinsp;2.5% or haptoglobin below the lower limit of detection or indirect bilirubin\u0026thinsp;\u0026gt;\u0026thinsp;2.0mg/dl), no active cancer, no history of solid organ or stem cell transplantation, mean corpuscular volume (MCV)\u0026thinsp;\u0026lt;\u0026thinsp;90fL, prothrombin time-international normalized ratio (PT-INR)\u0026thinsp;\u0026lt;\u0026thinsp;1.5, and creatinine\u0026thinsp;\u0026lt;\u0026thinsp;2.0mg/dl. Among them, 5 points are moderate risk, while 6\u0026ndash;7 points are highly predictive of TTP. This has certain clinical guiding for early diagnosis, intervention, and prognosis.\u003c/p\u003e \u003cp\u003eIn the pursuit of enhancing patient prognosis and outcomes, numerous challenges and complications associated with TTP treatment demand attention. Patients experiencing relapsed or refractory TTP exhibit slow and incomplete responses to standard TPE. While TPE, coupled with improved immunosuppressive and immunomodulatory therapies, has positively influenced patient prognosis, the mortality rate for TTP persists at 10\u0026ndash;20%, rising even higher in refractory cases \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.Current clinical strategies involve intensifying treatment through twice-daily plasma exchange and incorporating rituximab or other immunosuppressive therapies. Although these therapeutic advancements have positively impacted TTP outcomes, early diagnosis and prompt initiation of appropriate therapy remain crucial to achieving optimal results. TPE stands as the standard of care for iTTP, with its efficacy validated in randomized controlled trials \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAs new drugs are continually introduced, and clinical data is updated, therapeutic plasma exchange and hormone-based diagnostic and treatment programs are refined. This ongoing improvement is anticipated to offer a broader array of choices and options, fostering multidisciplinary and comprehensive diagnostic and treatment strategies for iTTP in the future.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproval was obtained from the Institutional Research Board of The Second Hospital of Jilin University. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors affirm that all data were internally generated, and no paper mill was utilized. WLY is the first auther and LJL is the corresponding author.RLS and TL collected the data.WLY,LJL and SWZ conceptualized and designed the experiments, analyzed the data.WLY,SWZ and RLS prepared figures 1-3. All authors contributed to the writing of the paper, provided editorial input, and approved the final draft.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe sincerely appreciate the financial support provided by the Natural Science Foundation of Jilin Province through the Jilin Science and Technology Development Program Project(YDZJ202301ZYTS065). Additionally, we acknowledge the invaluable assistance received from the Department of Oncology and Hematology and the Department of Critical Care Medicine at the Second Hospital of Jilin University for their contributions to this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availablility\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author confirms that all data are included in this published article. Furthermore, sources and data supporting the findings of this study were all publicly available at the time of submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproval was obtained from the Institutional Research Board of The\u0026nbsp;Second Hospital of Jilin University. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eElizabeth MS, Wenjing C, Huy PP, et al. Clinical factors and biomarkers predict outcome in patients with immune-mediated thrombotic thrombocytopenic purpura. \u003cem\u003eHaematologica\u003c/em\u003e. 01/01 2019;104(1):166-175. doi:10.3324/haematol.2018.198275\u003c/li\u003e\n\u003cli\u003eElliott MA, Heit JA, Pruthi RK, Gastineau DA, Winters JL, Hook CC. 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Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes. \u003cem\u003eBlood\u003c/em\u003e. Jul 10 2014;124(2):211-9. doi:10.1182/blood-2014-02-553131\u003c/li\u003e\n\u003cli\u003eAl-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN. Drug-induced thrombotic microangiopathy: a systematic review of published reports. \u003cem\u003eBlood\u003c/em\u003e. Jan 22 2015;125(4):616-8. doi:10.1182/blood-2014-11-611335\u003c/li\u003e\n\u003cli\u003eBendapudi PK, Li A, Hamdan A, et al. Impact of severe ADAMTS13 deficiency on clinical presentation and outcomes in patients with thrombotic microangiopathies: the experience of the Harvard TMA Research Collaborative. \u003cem\u003eBr J Haematol\u003c/em\u003e. Dec 2015;171(5):836-44. doi:10.1111/bjh.13658\u003c/li\u003e\n\u003cli\u003eMatsumoto M, Yagi H, Ishizashi H, Wada H, Fujimura Y. The Japanese experience with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. \u003cem\u003eSemin Hematol\u003c/em\u003e. Jan 2004;41(1):68-74. doi:10.1053/j.seminhematol.2003.10.009\u003c/li\u003e\n\u003cli\u003eSawler D, Parker A, Britto J, Goodyear MD, Sun HL. Time from suspected thrombotic thrombocytopenic purpura to initiation of plasma exchange and impact on survival: A 10-year provincial retrospective cohort study. \u003cem\u003eThromb Res\u003c/em\u003e. Sep 2020;193:53-59. doi:10.1016/j.thromres.2020.05.045\u003c/li\u003e\n\u003cli\u003eJoly BS, Coppo P, Veyradier A. An update on pathogenesis and diagnosis of thrombotic thrombocytopenic purpura. \u003cem\u003eExpert Review of Hematology\u003c/em\u003e. 2019/06/03 2019;12(6):383-395. doi:10.1080/17474086.2019.1611423\u003c/li\u003e\n\u003cli\u003eScully M, Hunt BJ, Benjamin S, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. \u003cem\u003eBr J Haematol\u003c/em\u003e. Aug 2012;158(3):323-35. doi:10.1111/j.1365-2141.2012.09167.x\u003c/li\u003e\n\u003cli\u003eSadler JE. Pathophysiology of thrombotic thrombocytopenic purpura. \u003cem\u003eBlood\u003c/em\u003e. 2017;130(10):1181-1188. doi:10.1182/blood-2017-04-636431\u003c/li\u003e\n\u003cli\u003eAsmis LM, Serra A, Krafft A, et al. Recombinant ADAMTS13 for Hereditary Thrombotic Thrombocytopenic Purpura. \u003cem\u003eN Engl J Med\u003c/em\u003e. Dec 22 2022;387(25):2356-2361. doi:10.1056/NEJMoa2211113\u003c/li\u003e\n\u003cli\u003eSadler JE, Moake JL, Miyata T, George JN. Recent advances in thrombotic thrombocytopenic purpura. \u003cem\u003eHematology Am Soc Hematol Educ Program\u003c/em\u003e. 2004:407-23. doi:10.1182/asheducation-2004.1.407\u003c/li\u003e\n\u003cli\u003eHovinga JAK, Vesely SK, Terrell DR, L\u0026auml;mmle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. \u003cem\u003eBlood\u003c/em\u003e. 2010/02/25/ 2010;115(8):1500-1511. doi:https://doi.org/10.1182/blood-2009-09-243790\u003c/li\u003e\n\u003cli\u003eSchleinitz N, Ebbo M, Mazodier K, et al. Rituximab as preventive therapy of a clinical relapse in TTP with ADAMTS13 inhibitor. \u003cem\u003eAm J Hematol\u003c/em\u003e. May 2007;82(5):417-8. doi:10.1002/ajh.20764\u003c/li\u003e\n\u003cli\u003eDeford CC, Reese JA, Schwartz LH, et al. Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura. \u003cem\u003eBlood\u003c/em\u003e. Sep 19 2013;122(12):2023-9; quiz 2142. doi:10.1182/blood-2013-04-496752\u003c/li\u003e\n\u003cli\u003eCallewaert F, Roodt J, Ulrichts H, et al. Evaluation of efficacy and safety of the anti-VWF Nanobody ALX-0681 in a preclinical baboon model of acquired thrombotic thrombocytopenic purpura. \u003cem\u003eBlood\u003c/em\u003e. Oct 25 2012;120(17):3603-10. doi:10.1182/blood-2012-04-420943\u003c/li\u003e\n\u003cli\u003eTse B, Buchholz M, Pavenski K. Management of immune thrombotic thrombocytopenic purpura with caplacizumab: a Canadian, single-centre, real-world experience. \u003cem\u003ePlatelets\u003c/em\u003e. Dec 2023;34(1)2157807. doi:10.1080/09537104.2022.2157807\u003c/li\u003e\n\u003cli\u003eZheng L, Zheng XL. How should caplacizumab be used for treatment of immune thrombotic thrombocytopenic purpura? \u003cem\u003eAnn Blood\u003c/em\u003e. Jun 30 2023;8doi:10.21037/aob-21-87\u003c/li\u003e\n\u003cli\u003eTersteeg C, Schiviz A, De Meyer SF, et al. Potential for Recombinant ADAMTS13 as an Effective Therapy for Acquired Thrombotic Thrombocytopenic Purpura. \u003cem\u003eArteriosclerosis Thrombosis and Vascular Biology\u003c/em\u003e. Nov 2015;35(11):2336-2342. doi:10.1161/atvbaha.115.306014\u003c/li\u003e\n\u003cli\u003eMoroniti JJ, Vrbensky JR, Nazy I, Arnold DM. Targeted ADAMTS-13 replacement therapy for thrombotic thrombocytopenic purpura. \u003cem\u003eJ Thromb Haemost\u003c/em\u003e. Dec 22 2023;doi:10.1016/j.jtha.2023.11.030\u003c/li\u003e\n\u003cli\u003eVerbeke L, Delforge M, Dierickx D. Current insight into thrombotic thrombocytopenic purpura. \u003cem\u003eBlood Coagul Fibrinolysis\u003c/em\u003e. Jan 2010;21(1):3-10. doi:10.1097/MBC.0b013e32833335eb\u003c/li\u003e\n\u003cli\u003eRock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. \u003cem\u003eN Engl J Med\u003c/em\u003e. Aug 8 1991;325(6):393-7. doi:10.1056/nejm199108083250604\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"thrombotic thrombocytopenic purpura, treatment, clinical analysis, plasma exchange, rituximab","lastPublishedDoi":"10.21203/rs.3.rs-4464305/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4464305/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis study aims to investigate the clinical characteristics, timing of intervention, diagnostic and treatment options, and prognostic factors in patients with immune thrombotic thrombocytopenic purpura (iTTP).Methods: We conducted a retrospective analysis of iTTP patients who visited the Second Hospital of Jilin University from January 2020 to April 2023, encompassing individuals with complete clinical data. The analysis included an examination of clinical manifestations and auxiliary test results.Results: The study involved 6 patients (5 males, 1 female) with an age range of 29\u0026ndash;84 years, and a median age of 58 years. Common clinical manifestations comprised thrombocytopenia, hematuria, soy sauce-colored urine, as well as neurological and psychiatric symptoms. All six patients underwent treatment with therapeutic plasma exchange(TPE), with three of them also receiving rituximab (3/6). The follow-up period ranged from 1 to 21 months, with a median of 10 months, concluding in April 2023. Of the six cases, three patients survived, while the remaining three succumbed in March 2021, July 2022, and March 2023, respectively.Conclusion: TTP diagnosis is often delayed due to its nonspecific clinical presentation. Accurate clinical diagnosis of TTP relies on assessing ADAMTS13 activity levels and genetic testing. Following PLASMIC-S guidelines, immediate plasma exchange and glucocorticoid therapy are recommended once diagnosis is suspected. Additionally, the evolving clinical landscape has seen an increasing number of patients benefiting from a combination of anti-CD20 monoclonal antibodies and other novel drugs. This expanding repertoire of treatment options enhances the multidisciplinary and comprehensive diagnostic and therapeutic strategy for iTTP.\u003c/p\u003e","manuscriptTitle":"Analysis of clinical factors in first diagnosis of immune thrombotic thrombocytopenic purpura with report of 6 cases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-07 23:17:25","doi":"10.21203/rs.3.rs-4464305/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"805e410d-f94c-4e73-bc5f-1a9bef22b872","owner":[],"postedDate":"June 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-29T03:32:27+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-07 23:17:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4464305","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4464305","identity":"rs-4464305","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}