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Objectives: Fluorescence resonance energy transfer (FRET)-based ADAMTS13 activity assays are critical for the diagnosis of thrombotic thrombocytopenic purpura. However, these assays are susceptible to interference. As iodide has been suggested to interfere in laboratory testing via fluorophore quenching or promotion, we aimed to determine whether iodinated contrast (Omnipaque) interferes with the ATS-13 ADAMTS13 Activity Assay 2.0., Methods: We evaluated the excitation, emission, and absorbance spectrum of Omnipaque alone and spiked in patient plasma with known ADAMTS13 activity and ADAMTS13 activity on Omnipaque alone, an abnormal control of patient plasma previously observed to display elevated baseline relative fluorescent units, and variable concentrations of patient plasma with known ADAMTS13 activity spiked with Omnipaque., Results: No atypical fluorescent peaks were observed on any sample (Omnipaque alone or spiked in plasma) between 250 and 700 nm. There was no difference in the mean ADAMTS13 activity among the various concentrations of plasma spiked with Omnipaque or plasma spiked with saline., Conclusions: Iodinated contrast does not appear to interfere-either via spectral overlap of the fluorophore or through physiologic inhibition of the ADAMTS13 enzyme-with ADAMTS13 activity FRET-based assays based on the findings from this in vitro analysis. Delaying sample collection for ADAMTS13 activity testing from suspected patients with thrombotic thrombocytopenic purpura following administration of iodinated radiocontrast agents is not necessary, and recent contrast administration should not yield erroneous ADAMTS13 activity results., (© American Society for Clinical Pathology, 2024.)

Acquired thrombotic thrombocytopenic purpura (acquired TTP) is a rare clinical syndrome caused by a decreased ADAMST13 activity, leading to systemic microvascular thrombotic events, with high mortality rates when the diagnosis and treatment are delayed. The authors report an acquired TTP in a patient with cerebrovascular disease. The aim is to emphasize the importance of considering atypical acquired TTP clinical presentations in order to optimize diagnostic and treatment approaches, minimize possible sequels, and improve the prognosis., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Barreto et al.)

Data are limited on the impact of commencing antiplatelet therapy on von Willebrand Factor Antigen (VWF:Ag) or von Willebrand Factor propeptide (VWFpp) levels and ADAMTS13 activity, and their relationship with platelet reactivity following TIA/ischaemic stroke. In this pilot, observational study, VWF:Ag and VWFpp levels and ADAMTS13 activity were quantified in 48 patients ≤4 weeks of TIA/ischaemic stroke (baseline), and 14 days (14d) and 90 days (90d) after commencing aspirin, clopidogrel or aspirin+dipyridamole. Platelet reactivity was assessed at moderately-high shear stress (PFA-100® Collagen-Epinephrine / Collagen-ADP / INNOVANCE PFA P2Y assays), and low shear stress (VerifyNow® Aspirin / P2Y12, and Multiplate® Aspirin / ADP assays). VWF:Ag levels decreased and VWFpp/VWF:Ag ratio increased between baseline and 14d and 90d in the overall population (P ≤ 0.03). In the clopidogrel subgroup, VWF:Ag levels decreased and VWFpp/VWF:Ag ratio increased between baseline and 14d and 90d (P ≤ 0.01), with an increase in ADAMTS13 activity between baseline vs. 90d (P ≤ 0.03). In the aspirin+dipyridamole subgroup, there was an inverse relationship between VWF:Ag and VWFpp levels with both PFA-100 C-ADP and INNOVANCE PFA P2Y closure times (CTs) at baseline (P ≤ 0.02), with PFA-100 C-ADP, INNOVANCE PFA P2Y and C-EPI CTs at 14d (P ≤ 0.05), and between VWF:Ag levels and PFA-100 INNOVANCE PFA P2Y CTs at 90d (P = 0.03). There was a positive relationship between ADAMTS13 activity and PFA-100 C-ADP CTs at baseline (R 2  = 0.254; P = 0.04). Commencing/altering antiplatelet therapy, mainly attributed to commencing clopidogrel in this study, was associated with decreasing endothelial activation following TIA/ischaemic stroke. These data enhance our understanding of the impact of VWF:Ag and VWFpp especially on ex-vivo platelet reactivity status at high shear stress after TIA/ischaemic stroke., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: A recent Phase 2/3 study in Japanese patients showed that caplacizumab was effective in treating immune-mediated thrombotic thrombocytopenic purpura (iTTP), with a low rate of iTTP recurrence. ADAMTS13 activity is monitored weekly during caplacizumab treatment to guide discontinuation of caplacizumab and consequently avoid exacerbations or relapse. The aim of this study was to assess changes in ADAMTS13 activity/inhibitor levels during caplacizumab treatment in this patient population., Methods: A post hoc analysis of the Phase 2/3 study in Japanese patients was conducted. Patients ≥ 18 years old with confirmed iTTP received 10 mg of caplacizumab daily in conjunction with therapeutic plasma exchange (TPE) and immunosuppression for 30 days post-TPE. Outcomes included time to recovery of ADAMTS13 activity, ADAMTS13 activity level at treatment end, incidence of ADAMTS13 inhibitor re-elevation (ie, inhibitor boosting) during treatment, time to platelet count recovery, number of days of TPE, and safety. Outcomes according to presence of inhibitor boosting were also assessed., Results: Nineteen patients had confirmed iTTP and were included in this analysis. Median (95% confidence interval) time to recovery of ADAMTS13 activity to ≥ 10%, ≥ 20%, and ≥ 60% was 14.6 (5.9-24.8), 18.5 (5.9-31.8), and 47.5 (18.5-60.9) days, respectively. Median (range) ADAMTS13 activity level at caplacizumab treatment end was 62.0% (29.0-101.0). Nine patients had ADAMTS13 inhibitor boosting. Delayed response of ADAMTS13 activity was observed in patients with inhibitor boosting. The median time to platelet count response and median number of TPE days were shorter in patients with inhibitor boosting compared with patients without inhibitor boosting. Rituximab was administered to almost all patients with inhibitor boosting (88.9%), after completion of TPE. Patients without inhibitor boosting who were treated with rituximab received it prior to completion of TPE. Only one patient experienced a recurrence, which occurred shortly after caplacizumab discontinuation due to an adverse event., Conclusions: In patients with iTTP, caplacizumab with TPE and immunosuppression may reduce the risk of ADAMTS13 inhibitor boosting if rituximab is administered early in the iTTP treatment period. Early administration of rituximab in addition to caplacizumab may prevent iTTP recurrence with inhibitor boosting., Trial Registration: NCT04074187., (© 2024. The Author(s).)

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare medical emergency for which a correct and early diagnosis is essential. As a severe deficiency in A Disintegrin And Metalloproteinase with ThromboSpondin type 1 repeats, member 13 (ADAMTS13) is the underlying pathophysiology, diagnostic strategies require timely monitoring of ADAMTS13 parameters to differentiate TTP from alternative thrombotic microangiopathies (TMAs) and to guide initial patient management. Assays for conventional ADAMTS13 testing focus on the enzyme activity and presence of (inhibitory) anti-ADAMTS13 antibodies to discriminate immune-mediated TTP (iTTP) from congenital TTP and guide patient management. However, diagnosis of iTTP remains challenging when patients present borderline ADAMTS13 activity. Therefore, additional biomarkers would be helpful to support correct clinical judgment. Over the last few years, the evaluation of ADAMTS13 conformation has proven to be a valuable tool to confirm the diagnosis of acute iTTP when ADAMST13 activity is between 10 and 20%. Screening of ADAMTS13 conformation during long-term patient follow-up suggests it is a surrogate marker for undetectable antibodies. Moreover, some non-ADAMTS13 parameters gained notable interest in predicting disease outcome, proposing meticulous follow-up of iTTP patients. This review summarizes non-ADAMTS13 biomarkers for which inclusion in routine clinical testing could largely benefit differential diagnosis and follow-up of iTTP patients.

Thrombotic thrombocytopenic purpura (TTP) is a disorder characterized by the formation of diffuse thromboses in small blood vessels, which can result in neurological and renal impairment, fever, and purpura, among additional sequelae. TTP-like syndromes are disease processes that have similar signs and symptoms as TTP but without a severe deficiency in ADAMTS13 levels. We present a case of a young male with advanced human immunodeficiency virus (HIV) and Streptococcus pneumoniae meningitis presenting with a thrombotic microangiopathy (TMA). Although his ADAMTS13 level was not suggestive of TTP, at 54.4% (normal low ADAMTS13: >66.8% activity; severe ADAMTS13 deficiency:  ≤ 10% activity), he improved only after plasmapheresis was initiated, supporting a diagnosis of a TTP-like syndrome likely due to his streptococcal meningitis. We discuss the importance of treating patients with TTP-like syndromes and advanced HIV with highly active antiretroviral therapy (HAART). We also highlight the increased prevalence of TMA and TTP among HIV patients and that many of these patients do not have a severe deficiency in levels of serum ADAMTS13., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Boland et al.)

Background: Thrombotic microangiopathy (TMA) is a syndrome associated with hemolytic anemia, thrombocytopenia, and various organ disorders. Thrombotic thrombocytopenic purpura (TTP) is a disease that develops when a disintegrin-like and metalloproteinase with thrombospondin type l motif 13 (ADAMTS13) activity decreases to < 10% of that in normal plasma, causing platelet thrombosis in microvessels throughout the body. Currently, ADAMTS13-deficient TMA is diagnosed as TTP. Systemic lupus erythematosus (SLE)-related TMA includes both acquired TTP, in which ADAMTS13 activity is significantly reduced, and secondary TMA, in which ADAMTS13 activity is not reduced. Both diseases have different prognoses., Case Presentation: An 11-year-old girl was admitted to our hospital on suspicion of TMA with thrombocytopenia and hemolytic anemia. Because the patient had hypocomplementemia, SLE-related TMA or complement-related TMA was considered. Therefore, we initiated plasma exchange (PE) for the patient. Subsequently, she fulfilled the pediatric SLE diagnostic criteria, and ADAMTS13 activity was shown to be decreased and the anti-ADAMTS13 antibody titer increased. She was thus diagnosed with acquired TTP caused by SLE. Treatment response was good as a platelet count and ADAMTS13 activity improved with three times of PE, followed by methylprednisolone pulse therapy and administration of mycophenolate mofetil. Renal pathology showed thrombus formation in glomerular arterioles and lupus nephritis categorized as Class III (A) of the International Society of Nephrology and the Renal Pathology Society classification. Because the patient was thought to be in the high-risk group of SLE, three courses of intravenous cyclophosphamide pulse therapy were administered as an additional induction therapy. No recurrence of TTP was observed., Conclusion: In SLE-related TMA, measurement of ADAMTS13 activity and the anti-ADAMTS13 antibody titer are necessary for diagnosis, and for predicting prognosis and recurrence of the disease; however, in the acute phase of immune-mediated TMA, it is important to initiate proper treatments even before knowing the results to improve prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Takagi, Kobayashi, Hirakata, Takei, Ogasawara, Yajima, Ikeuchi, Matsumoto, Ogawa, Handa, Matsumoto, Arakawa and Takizawa.)

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA) caused by decreased activity of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). Platelet-rich thrombi in small vessels lead to fragmentation of RBCs causing microangiopathic hemolytic anemia (MAHA). Therapeutic plasma exchange is life-saving and is the mainstay of the treatment of TTP. Higher dose IV steroids along with rituximab are used as an adjunct to plasma exchange. Our case report describes a 26-year-old healthy male who presented with new onset seizures and encephalopathy. Blood work demonstrated anemia, severe thrombocytopenia, elevated lactate dehydrogenase, decreased haptoglobin, and elevated creatinine, and peripheral blood smear showed marked schistocytosis indicating MAHA. Plasma exchange and high-dose steroids were started on a presumptive diagnosis of TTP. ADAMTS13 activity was undetectable and ADAMTS13 inhibitor levels were elevated. Rituximab and caplacizumab were then added. Symptoms of encephalopathy improved by day five and platelet counts started improving by day nine. After several days of plasma exchange, he showed a "clinical response" with several weeks of active treatment. The association between coronavirus disease 2019 (COVID-19) infection and the severity of TTP with multiorgan failure is not well understood yet. Although we describe a successful multimodal approach to the management of TTP, which we believe is secondary to COVID-19 infection, further research is warranted to analyze and understand the pathophysiology by which COVID-19 infection causes TTP. It would help in establishing standardized therapy in the future., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Mandyam et al.)

Plasma exchange is the commonly considered therapy for the treatment of thrombotic microangiopathy (TMA); however, it is not always mandatory. We treated a patient who presented with malignant hypertension (MH) complicated by TMA using antihypertensive therapy that was not accompanied by plasma exchange. A 38-year-old woman with photophobia, diarrhea, fever, and severely elevated blood pressure was referred to our hospital. Blood test results revealed thrombocytopenia and hemolytic anemia, and ascites were observed on the computed tomography images. Although TMA was suspected, plasma exchange was not performed because the platelet count was not markedly low. Her blood cell counts improved after antihypertensive treatment, and she was discharged. The patient is currently under therapy and remains stable. Thus, TMA secondary to MH may improve using antihypertensive therapy, without the need for invasive plasma exchange. Considering the platelet count may be helpful in deciding whether plasma exchange is required., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Asano et al.)

Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare disease that is defined as biallelic mutations of ADAMTS13 causing persistent absence of ADAMTS13 activity. The confirmed diagnosis requires a genetic study, and cTTP has never been previously reported in Taiwan. Our patient was a 29-year-old Taiwanese woman who presented with severe hyperbilirubinemia at birth. She had severe thrombocytopenia and hemolytic anemia at the age of 1, and another acute TTP event at the age of 7 triggered by an upper airway infection. Regular plasma replacement was started at age 12 based on a presumptive diagnosis of cTTP. Clinical diagnosis of cTTP, with undetectable ADAMTS13 activity and absence of ADAMTS13 inhibitor, was confirmed at age 27. A genetic study showed a previously reported mutation c.1921G to A, inherited from her father, and a maternally inherited, novel mutation at exon 12, c.1435+1dupG, which results in a splicing site change and frame shift. Reports of cTTP from East Asia, except Japan, are scarce. Some prevalent ADAMTS13 mutations are also race or region specific. With this report, we hope to raise awareness among physicians in Taiwan, promote early, proper diagnosis of cTTP, and reveal the true prevalence of cTTP in the Taiwanese population.

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal disorder caused by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency. Prompt identification/exclusion of TTP can thus be facilitated by rapid ADAMTS13 testing. The most commonly utilized (enzyme-linked immunosorbent assay [ELISA]-based) assay takes several hours to perform and so does not generally permit rapid testing., Objectives: To evaluate the utility of a new automated test for ADAMTS13 activity, the HemosIL AcuStar ADAMTS13 Activity assay, based on chemiluminescence and able to be performed on an ACL AcuStar instrument within 33 minutes., Patients/methods: This multicenter (n = 8) assessment included testing of more than 700 test samples, with similar numbers of prospective (n = 348) and retrospective (n = 385) samples. The main comparator was the Technozym ADAMTS13 Activity ELISA. We also assessed comparative performance for detection of ADAMTS13 inhibitors using a Bethesda assay., Results: Overall, the chemiluminescent assay yielded similar results to the comparator ELISA, albeit with slight negative bias. ADAMTS13 inhibitor detection was also comparable, albeit with slight positive bias with the AcuStar assay. Assay precision was similar with both assays, and we also verified assay normal reference ranges., Conclusions: The HemosIL AcuStar ADAMTS13 Activity assay provided results rapidly, which were largely comparable with the Technozym ADAMTS13 Activity ELISA assay, albeit lower on average. Conversely, inhibitor levels tended to be identified at a higher level on average. Thus, the HemosIL AcuStar ADAMTS13 Activity assay provides a fast and accurate means to quantitate plasma levels of ADAMTS13 for TTP/ADAMTS13 identification/exclusion, and potentially also for other applications., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: The PLASMIC score was recently published to aid in the early identification of thrombotic thrombocytopenic purpura (TTP) patients. This study aims to evaluate whether this score is suitable for Chinese suspected TTP patients and find the utility of patients' other characteristics in predicting severe ADAMTS13 deficiency., Methods: We retrospectively studied a Chinese cohort of 38 consecutive hospitalized patients with suspected TTP, ADAMTS13 test results, and other clinical data from September 2016 to May 2018. The predictive power of PLASMIC score in our cohort was evaluated, and patients' other characteristics, especially the high lactate dehydrogenase/the upper limit of normal (LDH/ULN), were studied to determine their distinguishing ability for TTP patients., Results: In this Chinese cohort, 17 patients were diagnosed with TTP according to ADAMTS13 activity results. When dichotomized at intermediate-high risk (scores 5-7) vs low risk (scores 0-4), the PLASMIC score predicted TTP with a sensitivity of 100%, a specificity of 9.52%, and a misdiagnosis rate of 90.48%. And the LDH/ULN alone, or plus platelet count, reticulocyte percentage and indirect bilirubin (IBIL) both had excellent predictive power (area under the curve [AUC] 0.937, 95% confidence interval [CI] 0.863-1.000, P = .000, and AUC 0.994, 95% CI 0.980-1.000, P = .000, respectively). The model including platelet count, reticulocyte percentage, IBIL, and LDH/ULN ratio had a sensitivity of 100%, a specificity of 95.2%, and a misdiagnosis rate of 4.8%., Conclusions: A modified PLASMIC score plus LDH/ULN ratio might be more suitable for identifying ADAMTS13 deficiency patients, especially for making an earlier diagnosis, guiding the immediate and reasonable plasma exchange, and also avoiding unnecessary allocation of plasma., (© 2019 Wiley Periodicals, Inc.)

Background: Thrombotic microangiopathy (TMA) with non-deficient ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13) outcome is unknown hence the survival analysis correlating with ADAMTS-13 activity is conducted in Malaysia., Methods: This was a retrospective epidemiological study involving all cases of TMA from 2012-2016., Results: We evaluated 243 patients with a median age of 34.2 years; 57.6% were female. Majority of the patients were Malay (62.5%), followed by Chinese (23.5%) and Indian (8.6%). The proportion of patients with thrombotic thrombocytopenic purpura (TTP) was 20.9%, 72.2% of which were acquired while 27.8% were congenital. Patients with ADAMTS-13 activity ≥5% had a four-fold higher odds of mortality compared to those with ADAMTS-13 activity <5% (odds ratio: 4.133, P =0.0425). The mortality rate was 22.6% (N=55). Most cases had secondary etiologies (42.5%), followed by acquired TTP (16.6%), atypical hemolytic uremic syndrome (HUS) or HUS (12.8%) and congenital TTP (6.4%). Patients with secondary TMA had inferior overall survival ( P =0.0387). The secondary causes comprised systemic lupus erythematosus (30%), infection (29%), pregnancy (10%), transplant (8%), malignancy (6%), and drugs (3%). Transplant-associated TMA had the worst OS ( P =0.0016) among the secondary causes. Plasma exchange, methylprednisolone and intravenous immunoglobulin were recorded as first-line treatments in 162 patients, while rituximab, bortezomib, vincristine, azathioprine, cyclophosphamide, cyclosporine, and tacrolimus were described in 78 patients as second-line treatment., Conclusion: This study showed that TMA without ADAMTS-13 deficiency yielded inferior outcomes compared to TMA with severeADAMTS-13 deficiency, although this difference was not statistically significant., Competing Interests: Authors' Disclosures of Potential Conflicts of Interest: No potential conflicts of interest relevant to this article were reported.

Cobalamin C (cblC) deficiency is the most commonly inherited inborn error of vitamin B12 metabolism. It is characterized by multisystem involvement with severe neurological, hematological, renal and cardiopulmonary manifestations. Disease is most commonly diagnosed early in the first decade of life. We report a case of a 20-year-old woman who developed severe pulmonary arterial hypertension while under nephrologic follow-up for chronic kidney disease. She had initially presented at 14 years of age with visual disturbance and acute renal failure and been diagnosed with thrombotic thrombocytopenic purpura on the basis of kidney biopsy findings of thrombotic microangiopathy and compatible ADAMTS13 (a disentegrin and metalloproteinase with a thrombospondin type 1 motif member 13). When cblC deficiency was eventually diagnosed, remarkable improvement in cardiopulmonary function was evident upon initiation of treatment. This case highlights the importance of a timely diagnosis and initiation of treatment for cblC deficiency. Clinical diagnosis may be challenged by asynchronous organ symptom presentation and by misleading laboratory tests, in this case: an initial low ADAMTS13. A simple test of plasma homocysteine level should be encouraged in cases of thrombotic microangiopathy and/or pulmonary artery hypertension.

Background: The PLASMIC score was recently described as a convenient tool for predicting ADAMTS13 activity ≤10% in patients with possible thrombotic thrombocytopenic purpura (TTP), while awaiting the results of this send-out test. The purpose of this study was to validate the PLASMIC score at our University Medical Center., Methods: Apheresis records were reviewed from 2008 to 2017 to identify patients who received plasma exchange (PLEX) for suspected TTP. The ADAMTS13 activity and PLASMIC scoring criteria were recorded, and the PLASMIC score was calculated., Results: Of the 41 patients identified, 20 met inclusion criteria, of which 7 patients had ADAMTS13 activity ≤10%. Intermediate and high PLASMIC scores had 100% sensitivity, 46.2% specificity, 50% positive predictive value (PPV), and 100% negative predictive value (NPV)., Conclusion: These results are consistent with the original validation study of the PLASMIC score, supporting the efficacy of the PLASMIC score and validating its use at our institution., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Altered levels of von Willebrand factor (vWF) and ADAMTS13 can promote thrombosis and disturb blood flow in kidney microcirculations. We investigated the association of serum vWF:ADAMTS13 ratio in relation to decline in kidney function., Study Design: Prospective cohort study., Setting & Participants: 2,479 individuals (mean age, 65.1±5.9 [SD] years; 43% men) from the population-based Rotterdam Study., Predictors: vWF, ADAMTS13, and vWF:ADAMTS13 ratio., Outcomes & Measurements: Annual decline in estimated glomerular filtration rate (eGFR), halving of eGFR, and new-onset eGFR<60mL/min/1.73m 2 were assessed., Results: During a median follow-up of 11 (range, 7.81-13.57) years, 500 cases of new-onset eGFR<60mL/min/1.73m 2 occurred. The population had a mean eGFR decline of 0.96±0.92mL/min/1.73m 2 per year. Higher vWF:ADAMTS13 ratio was associated with steeper annual decline in eGFR (difference, -0.06 [95% CI, -0.09 to -0.02] mL/min/1.73m 2 per year) and higher risk for new-onset eGFR<60mL/min/1.73m 2 (OR, 1.13; 95% CI, 1.01-1.27). Likewise, higher vWF:ADAMTS13 ratio was associated with higher risk for halving of eGFR (OR, 1.40; 95% CI, 1.02-1.93). After adjustment for cardiovascular risk factors and blood group, effect estimates remained the same., Limitations: No data available for albuminuria. Participants were classified based on a single measurement of vWF and ADAMTS13., Conclusions: In this population-based study, we showed that higher vWF:ADAMTS13 ratio is associated with decline in kidney function, suggesting a role of elevated prothrombotic factors in the development and progression of kidney disease., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Differential diagnosis between thrombotic thrombocytopenic purpura (TTP) and other thrombotic microangiopathies (TMA) is usually difficult because of frequently overlapping clinical presentations. Severely depressed ADAMTS13 activity (<10 %) seems distinctive for TTP because of its pathogenetic role. However a long debate exists in the literature about its sensibility and specificity. Our aim was to search for clinical differences between TMA patients referred to our laboratory, comparing them for protease activity <10 versus ≥10 %. ADAMTS13 activity ≥10 % patients (n = 73) showed a higher prevalence of drug- (p = 0.005) and cancer-associated (p < 0.001) TMA. Mean platelet count and renal dysfunction prevalence was lower (p < 0.001), while neurological impairment was more frequent (p = 0.001) in the <10 % ADAMTS13 activity group (n = 109), confirming previous literature findings. When taken neurological manifestations singularly, epilepsy (p = 0.04), focal motor deficit (p < 0.001) and cranial nerve palsy (p = 0.007) were more frequent in the <10 % activity group. In our case series, a <10 % ADAMTS13 activity depicts a group of patients with clinical features similar to TTP patients. Focal motor impairment or epileptic manifestations could further address toward a TTP diagnosis. Studies about treatment efficacy and follow-up are advised to determine whether laboratory findings can guide therapeutic decisions.

Background and Objectives: Acute renal impairment is observed in 11%-23% of patients with congenital thrombotic thrombocytopenic purpura (TTP) and deficiency of a disintegrin and metalloprotease with thrombospondin motifs 13 (ADAMTS13, a metalloprotease that cleaves von Willebrand factor [VWF] multimers), a substantial percentage of whom develop CKD during follow-up., Design, Setting, Participants, & Measurements: Here we investigated whether, in 18 patients with congenital recruited from 1996 to 2013 who fulfilled inclusion criteria, acute renal involvement occurred during bouts segregated with lower secretion and activity levels of ADAMTS13 mutants. We performed expression studies and a sensitive recombinant VWF (rVWF) A1-A2-A3 cleavage test (detection limit, 0.78% of normal ADAMTS13 activity)., Results: A higher risk of acute renal impairment during bouts was observed in patients with childhood (<18 years) onset (odds ratio [OR], 24.6 [95% confidence interval (CI), 1.11 to 542.44]) or a relapsing (≥1 episode per year) disease (OR, 54.6 [95% CI, 2.25 to 1326.28]) than in patients with adulthood onset or long-lasting remission, respectively. Whatever the age at onset, patients with acute renal impairment had mutations different from those in patients without renal involvement. Moreover, mutations in patients with acute renal impairment compared with those in patients without renal involvement caused lower in vitro rADAMTS13 secretion (1.33% versus 12.5%; P<0.001) and residual activity (0.11% versus 3.47%; P=0.003). rADAMTS13 secretion ≤3.75% and residual activity ≤0.4% best discriminated patients with renal impairment (receiver-operating characteristic curve sensitivity, 100% and 100%; specificity, 100% and 83.3%, respectively; logistic regression OR, 325 [95% CI, 6 to 18339] and 91.7 [95% CI, 3.2 to 2623.5], respectively). All mutations found in patients with childhood onset or relapsing disease were associated with acute renal impairment during bouts, confirming the link between acute renal impairment and early onset or a relapsing course. ADAMTS13 activity levels in vivo, measured in patients' serum by rVWF A1-A2-A3 cleavage test, correlated with in vitro rADAMTS13 mutant activity (r=0.95; P<0.001)., Conclusions: In congenital TTP, renal impairment and relapsing disease might be predicted by measurements of in vitro rADAMTS13 secretion and activity levels and in vivo serum ADAMTS13 activity., (Copyright © 2015 by the American Society of Nephrology.)

Background: Severe deficiency of ADAMTS13 activity leads to von Willebrand factor (VWF) ultralarge multimers with high affinity for platelets, causing thrombotic thrombocytopenic purpura. Other pathological conditions with moderate ADAMTS13 activity exhibit a thrombotic risk. We examined the ADAMTS13 activity in systemic lupus erythematosus (SLE) and its value as a thrombotic biomarker., Methods: ADAMTS13 activity, VWF antigen and multimeric structure, and vascular cell adhesion molecule 1 (VCAM-1) were measured in plasma samples from 50 SLE patients and 50 healthy donors. Disease activity (systemic lupus erythematosus disease activity index; SLEDAI) and organ damage (systemic lupus international collaborating clinics) scores, thrombotic events, antiphospholipid syndrome (APS) and antiphospholipid antibodies (aPLs) were registered., Results: SLE patients showed decreased ADAMTS13 activity and high VWF levels compared with controls (66 ± 27% vs. 101 ± 8%, P < 0.01, and 325 ± 151% vs. 81 ± 14%, P < 0.001). VCAM-1 levels were higher in SLE patients (P < 0.05). Considering three groups of SLE patients depending on ADAMTS13 activity (>60%, 60-40% and <40%), comparative analysis showed significant association between ADAMTS13 activity and SLEDAI (P < 0.05), presence of aPLs (P < 0.001), APS (P < 0.01) and thrombotic events (P < 0.01). Reduced ADAMTS13 activity together with increased VWF levels were especially notable in patients with active disease and with aPLs., Conclusion: ADAMTS13 activity, in combination with other laboratory parameters, could constitute a potential prognostic biomarker of thrombotic risk in SLE., (© The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

The complex relation between thrombotic thrombocytopenic purpura (TTP) and pregnancy is concisely reviewed. Pregnancy is a very strong trigger for acute disease manifestation in patients with hereditary TTP caused by double heterozygous or homozygous mutations of ADAMTS13 (ADisintegrin And Metalloprotease with ThromboSpondin type 1 domains, no. 13). In several affected women disease onset during their first pregnancy leads to the diagnosis of hereditary TTP. Without plasma treatment mother and especially fetus are at high risk of dying. The relapse risk during a next pregnancy is almost 100% but regular plasma transfusion starting in early pregnancy will prevent acute TTP flare-up and may result in successful pregnancy outcome. Pregnancy may also constitute a mild risk factor for the onset of acute acquired TTP caused by autoantibody-mediated severe ADAMTS13 deficiency. Women having survived acute acquired TTP may not be at very high risk of TTP relapse during an ensuing next pregnancy but seem to have an elevated risk of preeclampsia. Monitoring of ADAMTS13 activity and inhibitor titre during pregnancy may help to guide management and to avoid disease recurrence. Finally, TTP needs to be distinguished from the much more frequent hypertensive pregnancy complications, preeclampsia and especially HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelet count) syndrome., (© 2015 Elsevier Ltd. All rights reserved.)

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA), related to a severe functional deficiency of ADAMTS13 activity (<10% of normal). ADAMTS13 activity is thus crucial to confirm the clinical suspicion of TTP, to distinguish it from other TMAs, and to perform the follow-up of TTP patients., Material and Methods: We compared the performance of the commercial chromogenic assay Technozym ADAMTS13 Activity ELISA (chromogenic VWF73 substrate, Chr-VWF73, Technoclone, Vienna, Austria), to that of our in-house FRETS-VWF73 used as reference method. A large group of 247 subjects (30 healthy volunteers and 217 patients with miscellaneaous TMAs) was studied., Results: The lower limit of detection of the Chr-VWF73 was 3%, which is well adapted to the clinically relevant threshold for TTP diagnosis (10%). Our results showed a reasonable agreement between FRETS-VWF73 and Chr-VWF73 assays to distinguish samples with an ADAMTS13 activity <10% from those with an ADAMTS13 activity >10%. However, Chr-VWF73 assay provided false negative results in ~12% of acute TTP patients. Inversely, the Chr-VWF73 assay globally underestimated ADAMTS13 activity in detectable values ranging from 11 to 100% (with a great variability compared to FRETS-VWF73), which may be a concern for the follow-up of TTP patients in remission., Conclusion: In-house assays developed and performed by expert laboratories remain the reference methods that should be used without limitation to control values provided by commercial assays when needed. Also, the development of an international reference preparation will be crucial to improve standardization., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Unlabelled: We report on our patient (case 2) who experienced a first acute episode of thrombotic thrombocytopenic purpura (TTP) at the age of 19 years during her first pregnancy in 1976 which ended in a spontaneous abortion in the 30th gestational week. Treatment with red blood cell concentrates was implemented and splenectomy was performed. After having suffered from several TTP episodes in 1977, possibly mitigated by acetylsalicylic acid therapy, an interruption and sterilization were performed in 1980 in her second pregnancy thereby avoiding another disease flare-up. Her elder sister (case 1) had been diagnosed with TTP in 1974, also during her first pregnancy. She died in 1977 during her second pregnancy from a second acute TTP episode., Diagnosis: In 2013 a severe ADAMTS13 deficiency of <10% without detectable ADAMTS13 inhibitor was repeatedly found. Investigation of the ADAMTS13 gene showed that the severe ADAMTS13 deficiency was caused by compound heterozygous ADAMTS13 mutations: a premature stop codon in exon 2 (p.Q44X), and a missense mutation in exon 24 (p.R1060W) associated with low but measurable ADAMTS13 activity., Conclusion: Genetic analysis of the ADAMTS13 gene is important in TTP patients of all ages if an ADAMTS13 inhibitor has been excluded.

The increased understanding of the pathophysiology of both atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP) in recent years has led to significant therapeutic advances for both conditions. These advances have placed an increased emphasis on a more rapid differentiation of both disorders which remain clinical diagnoses. In particular, recent data demonstrating the effectiveness of complement inhibition in patients with aHUS have increased the need for a more rapid and accurate differentiation of aHUS and TTP. Previously utilized criteria have used the presence or absence of neurologic or renal injury and the pretreatment ADAMTS13 activity to differentiate aHUS from TTP. The use of presenting clinical symptoms and findings alone to differentiate these conditions is problematic given their overlapping clinical presentations. Similarly, the use of the pretreatment ADAMTS13 activity alone to differentiate aHUS from TTP is also problematic, and could lead to the inappropriate witholding of plasma exchange (PEX) therapy. However, when used collectively, the pretreatment clinical findings (symptoms and laboratory data) and ADAMTS13 activity in the context of the patient's response to PEX therapy can allow for a more effective differentiation of these two disorders in a timely fashion that will allow for the prompt initiation of the most appropriate therapy., (Copyright © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)