Diagnosis Of Thrombocytopenic Purpura Research Articles

The challenging follow-up of pregnancy in women with known thrombotic thrombocytopenic purpura: a single-center experience of a preemptive management protocol.

Although thrombotic thrombocytopenic purpura frequently affects women of childbearing age, there is no clear recommendation for the management of subsequent pregnancies in women with established thrombotic thrombocytopenic purpura. This single-center, retrospective, observational study included all women with hereditary thrombotic thrombocytopenic purpura or immune thrombotic thrombocytopenic purpura who had had at least one subsequent pregnancy after thrombotic thrombocytopenic purpura diagnosis between 2003 and 2022. The strategy comprised weekly surveillance of platelet count during pregnancy (and quarterly monitoring of ADAMTS13 activity) for women with immune thrombotic thrombocytopenic purpura, without any routine prophylactic treatment. In case of thrombocytopenia < 150,000/mm3 (with or without hemolysis relapse), women with hereditary thrombotic thrombocytopenic purpura systematically received plasma infusions twice weekly until platelet count normalized. A total of 13 patients were included (7 with hereditary thrombotic thrombocytopenic purpura and 6 with immune thrombotic thrombocytopenic purpura, with 20 planned pregnancies (11 and 9, respectively). All pregnancies resulted in live births, and all mothers survived.There was a marked improvement in pregnancy terms in the hereditary thrombotic thrombocytopenic purpura group compared to index pregnancies (37 [35;39] versus 31 [24;38] weeks, p = 0.037) and birth weights (3265 [3029;3410] versus 2160 [1240;2705] grams, p = 0.016), with need for plasma support mostly starting during the third trimester (5/7 patients, 7/11 pregnancies). A single hereditary thrombotic thrombocytopenic purpura relapse occurred, with rapid resolution after plasma support intensification. There were no relapses in the immune thrombotic thrombocytopenic purpura group, with ADAMTS13 activity systematically above 40% during all monitored pregnancies. These real-life data support the feasibility of a preemptive approach to pregnancy monitoring in women with known thrombotic thrombocytopenic purpura who undergo active surveillance within a multidisciplinary network.

A-154 Cost-effectiveness of On-site Vs Send-out Measurement of ADAMTS13 Activity in the Management of Acquired Thrombotic Thrombocytopenic Purpura

Abstract Background Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy (TMA) caused by congenital or acquired severe deficiency of disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13), an enzyme cleaving von Willebrand factor (VWF). ADAMTS-13 deficiency leads to the accumulation of ultra-large VWF multimers, and subsequent platelet aggregation and microthrombi formation. Aside clinical symptoms, the diagnosis of TTP is based thrombocytopenia, hemolytic anemia with the presence of schistocytes, and severely reduced activity of ADAMTS-13 (&amp;lt;10%). As TTP is a life-threatening condition, it is of great importance to shorten the time to the treatment, and according to the French recommendations, the triplet therapy including plasma exchange (PEX), rituximab, caplacizumab, plus corticosteroids, must be administered to patients with suspected TTP until the results of ADAMTS-13 was obtained, and be pursued only in the case of deficiency. Therefore, a rapid ADAMTS-13 testing is critical for early diagnosis and optimal management of acute TTP. Methods We compared the cost-effectiveness of a strategy based on on-site measurement of ADAMTS-13 activity using a rapid fully automated chemiluminescent assay (HemosIL AcuStar ADAMTS-13) vs its centralized measurement in a reference laboratory, as it is currently the case at our institution. For that purpose, we created two scenarios based on either its local measurement with a maximum time-to-result of 16 h (assay performed during daytime, 7/7) or its centralized measurement with a median time-to-result of 4 days (range: 2–8, as demonstrated from the 2018–2021 estimates). The triplet therapy was hypothesized to be started on admission and stopped if ADAMTS-13 activity was &amp;gt;10%. In case of ADAMTS-13 activity &amp;lt;10%, an inhibitor screening would be performed at the reference laboratory, as this assay was not expected to be locally implemented. For the calculation, we considered the costs of reagent, shipping/handling of samples to the reference laboratory, laboratory staff workload, reimbursement rates, and treatments administered in patients with suspected TTP until availability of the ADAMTS-13 result. Results Based on 2018 to 2021 estimates, there was a mean of 60 prescriptions of ADAMTS-13 activity per year. Most were for the follow-up of TTP patients and for patients with non-TTP TMA. Only seven were for the diagnosis of acute TTP, as suggested by the French score, which was confirmed in four cases (mean values). The local measurement of ADAMTS-13 activity was found to be cost-effective with a 16%-reduction of the costs compared to its centralized measurement in those seven patients with suspected TTP during the first 4 days. Conclusion Together with its short turnaround time (33 min) and its full automation, our results suggest that the HemosIL AcuStar ADAMTS-13 activity assay could be an assay of choice to rapidly measure ADAMTS-13 activity in the plasma and thus to establish the diagnosis of acute TTP in emergency settings. Considering the local costs, using the strategy based on the local evaluation of ADAMTS-13 activity led to a 16%-reduction of the overall costs during the first 4 days after admission of the seven patients with suspected acute TTP.

Measuring ADAMTS-13 activity to diagnose thrombotic thrombocytopenic purpura: a novel, fast fiber-optic surface plasmon resonance immunoassay

BackgroundThrombotic thrombocytopenic purpura (TTP) is characterized by severe ADAMTS-13 activity deficiency (<10%). Diagnostic testing is challenging because of unavailability, high cost, and expert technician requirement of ADAMTS-13 enzyme assays. Cost-effective, automated fiber-optic surface plasmon resonance (FO-SPR) platforms show potential for developing diagnostic tests. Yet, FO-SPR has never been explored to measure enzymatic activities. ObjectivesTo develop an easy-to-use ADAMTS-13 activity assay utilizing optical fibers to rapidly diagnose TTP. MethodsThe ADAMTS-13 activity assay was designed and optimized using FO-SPR technology based on a previously described enzyme-linked immunosorbent assay setup. A calibration curve was generated to quantify ADAMTS-13 activity in plasma of healthy donors and patients with acute immune-mediated TTP (iTTP), hemolytic uremic syndrome, or sepsis. ADAMTS-13 activity data from FO-SPR and fluorescence resonance energy transfer-based strategies (FRETS)-VWF73 reference assays were compared. ResultsAfter initial assay development, optimization improved read-out magnitude and signal-to-noise ratio and reduced variation. Further characterization demonstrated a detection limit (6.8%) and inter-assay variation (Coefficient of variation, 7.2%) that showed good analytical sensitivity and repeatability. From diverse plasma samples, only plasma from patients with acute iTTP showed ADAMTS-13 activities below 10%. Strong Pearson correlation (r = 0.854) between FO-SPR and reference FRETS-VWF73 assays were observed for all measured samples. ConclusionsA fast ADAMTS-13 activity assay was designed onto automated FO-SPR technology. Optimization resulted in sensitive ADAMTS-13 activity measurements with a detection limit enabling clinical diagnosis of TTP within 3 hours. The FO-SPR assay proved strong correlation with the reference FRETS-VWF73 assay. For the first time, this assay demonstrated the capacity of FO-SPR technology to measure enzymatic activity in pre-clinical context.

Thrombotic thrombocytopenic purpura in a patient on long-term alpha-interferon therapy for essential thrombocythemia: a case report

BackgroundThrombotic thrombocytopenic purpura (TTP) is rare and severe thrombotic microangiopathy characterized by thrombocytopenia, hemolytic anemia, and renal dysfunction. In contrast, essential thrombocythemia (ET) is a myeloproliferative disease associated with an abnormal increase in platelet numbers. Previous studies reported several cases of the development of ET in patients with TTP. However, the case of an ET patient complicated with TTP has not been previously reported. In this case study, we present a patient with TTP who was previously diagnosed with ET. Therefore, to the best of our knowledge, this is the first report of TTP in ET.Case presentationA 31-year-old Chinese female who was previously diagnosed with ET presented with anemia and renal dysfunction. The patient had been on long-term treatment with hydroxyurea, aspirin, and alpha interferon (INF-α) for ten years. The diagnosis of TTP was confirmed by clinical features, schistocytes noted on the peripheral blood smear, and lower ADAMTS13 activity (8.5%), together with the renal biopsy results. INF-α was discontinued, and the patient was then treated with plasma exchange and corticosteroids. After one year of follow-up, the patient had a normal hemoglobin level and platelet numbers, and her ADAMTS13 activity had improved. However, the patient’s renal function remains impaired.ConclusionsWe report a case of an ET patient complicated with TTP that was possibly due to INF-α, highlighting the potential complications associated with long-term ET therapy. The case also highlights the importance of considering TTP in patients with pre-existing ET who present with anemia and renal dysfunction, extending the spectrum of known studies.

A case of rectal cancer with immune thrombocytopenic purpura that achieved a complete response to continued chemotherapy with eltrombopag

A 73-year-old male patient with postoperative recurrent rectal cancer developed thrombocytopenia after XELOX therapy. Thrombocytopenia persisted despite chemotherapy discontinuation;therefore, he was referred to our department for further evaluation. Bone marrow specimen examination revealed increased immature megakaryocytes and blood test results revealed elevated platelet-associated immunoglobulin G (PA-IgG) levels, leading to immune thrombocytopenic purpura diagnosis. His platelet count recovered after prednisolone therapy. Eltrombopag treatment was introduced considering thrombocytopenia secondary to chemotherapy resumption for rectal cancer. FOLFIRI therapy was continued without platelet count reduction, and PA-IgG levels decreased over time. The patient continued chemotherapy with eltrombopag and achieved a complete treatment response.

Thrombotic thrombocytopenic purpura developed after pegylated interferon treatment for hepatitis B infection

BackgroundThrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia. It is related to severe deficiency in ADAMTS13, which is usually acquired via ADAMTS13 autoantibodies or inherited via mutations of the ADAMTS13 gene. The etiology of acquired TTP including HIV infection, pregnancy, autoimmune disease, organ transplantation, drugs, malignancy and so on. Here, we firstly reported a patient diagnosed as acquired TTP after pegylated interferon therapy for hepatitis B and COVID-19 vaccination.Case presentationA 36-year-old male attended to our unit with a five-day history of intermittent hematuria and progressive fatigue on January 5th, 2022. He had a 13 years history of hepatitis B infection and undergone pegylated interferon treatment (which was paused for two months because of COVID-19 vaccination) for nearly 3 years. Laboratory evaluation revealed a haemoglobin level of 61 g/L, platelet count of 11 × 109/L, lactate dehydrogenase 2133 U/L. The direct and indirect Coombs test were both negative. On a peripheral blood smear, there were about 18.8% schistocytes. Meanwhile, the results of ADAMTS 13 activity and antibody were < 5% and 181.34 ng/ml (131.25–646.5), respectivelyConclusionThis case firstly reported the rare complication of TTP after pegylated interferon treatment for hepatitis B and COVID-19 vaccine injection. This unique sign warrants more attention as an early cue of diagnosis of TTP and be aware of the rarity adverse effect of interferon therapy and COVID-19 vaccination.

Plasmic (PLASMICkid) Score for Pediatric Thrombotic Thrombocytopenic Purpura

Introduction: Thrombocytopenic purpura (TTP) is an extremely rare disease in children, yet potentially life-threatening without timely therapeutic plasma exchange (TPE). Gold standard for diagnosis is ADAMTS 13 activity </= 10, which may not be readily available, take days to result and delay treatment. PLASMIC score was devised and validated to make a presumptive diagnosis of TTP and initiate early intervention in adults with thrombotic microangiopathy (TMA). It allots one point for each variable for maximum score of 7, and is intended to be used only with thrombocytopenia (platelets < 150,000) and schistocytes on peripheral smear. The variables are thrombocytopenia (Platelets < 30,000/L), evidence of hemoLysis (reticulocyte count > 2.5%, haptoglobin undetectable, or indirect bilirubin > 2.0 mg/dL), absence of Active cancer (or no cancer treatment within the past year), no solid-organ or Stem-cell transplant, MCV < 90 fL, INR < 1.5, and Creatinine < 2.0 mg/dL. Patients with PLASMIC score of 0-4 considered low risk group with 0% risk, 5 as intermediate risk group with 6% risk, and 6 or 7 as high-risk group with 72% risk of severe ADAMTS-13 deficiency (activity < 10%). Patients in intermediate and high-risk group should start TPE while awaiting ADAMTS-13 activity levels. All parameters could potentially be applied in children except serum creatinine. However, there is not enough data to validate the score in children. There are two pediatric case reports where PLASMIC score was used to support or predict TTP. Of note, age of the patients in these reports was 15 - 16 years, and PLASMIC score was used without modifications. In an adult, creatinine of 2 mg/dL would roughly be 50% reduction in renal function, but could indicate severe kidney dysfunction in children, especially the young. Therefore, an estimated glomerular filtration rate (eGFR) would be a better parameter for kidney function in children. We modified the PLASMIC score (PLASMICkid) with eGFR > 50ml/min/1.73m2 substituting serum creatinine < 2 mg/dL. We aimed to assess the applicability of our PLASMICkid score in pediatric patients with TTP. Methods: We identified patients ≤ 19 years of age with TTP and patients who received TPE for diagnosis of TMA from 2010 to 2021 via an administrative database and performed retrospective chart review. Patients who did not have one or more parameters to calculate PLASMICkid score, or did not have ADAMTS-13 activity were excluded. Serum creatinine based revised bedside Schwartz equation was used to calculate eGFR, to be used in place of serum creatinine. A similar scoring system as the original score retaining rest of the parameters, was used to stratify risk for TTP. Results: We had a total of 30 patients who met the inclusion criteria, with a mean age of 9 years (range 11 months to 19 years). Severe ADAMTS-13 deficiency with activity level ≤10% was noted in 14/30 patients. All patients with severe deficiency had scores of 6 or 7 with 100% sensitivity (p-value 0.002, Table). Interestingly, we could apply it to a child as young as 11 months with an ADAMTS-13 activity of 10%, who had a score of 5 indicating intermediate risk for TTP. It also showed 100% negative predictive value, with 8/8 patients with a score of 0-4 having normal ADAMTS-13 activity. Conclusion: This is the first study to our knowledge that has attempted to modify the PLASMIC score for pediatric population. None of the patients with TTP had a PLASMICkid score of < 5 making it a fairly sensitive tool in presumptive diagnosis of pediatric TTP. PLASMICkid would need validation in larger cohorts, however using eGFR instead of serum creatinine in PLASMIC score can increase sensitivity in identifying high risk pediatric patients needing early TPE. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

AB1514 AN UNUSUAL ASSOCIATION BETWEEN THROMBOTIC THROMBOCYTOPENIC PURPURA AND PRIMARY ANTIPHOSPHOLIPID SYNDROME

BackgroundThrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic haemolytic anemia, consumption thrombocytopenia and organ injury, particularly kidney failure and neurological manifestation1.Two forms are distinguished: the hereditary one, caused by a deficit of the metalloprotease ADAMTS13, and the idiopathic one characterized by the presence of antibodies directed against ADAMTS13. The second one is the most common. There are various subgroups of acquired TTP associated with HIV infection, sepsis, pregnancy, autoimmune disease, disseminated malignancies and drugs. Antiphospholipid syndrome (APS) is a clinical immunological condition characterized by thromboembolic events, repetead miscarriages or stillbirth and thrombocytopenia; it can be a primary disorder or due to connective tissue disease, in particular systemic lupus erythematosus2.ObjectivesWe describe a case of TTP associated with a primary APS. The real clinical challenge lies in the differential diagnosis between TTP and anti-phospholipid antibody syndrome.MethodsA 37-year-old man presented to the emergency department for short-term episodes of anesthesia of the right upper limb and face with spontaneous resolution. In his past medical history, he suffered of antiphospholipid syndrome treated with warfarin. Upon admission, blood tests revealed severe thrombocytopenia, haemolytic anemia with schistocytes on peripheral blood smear, low thrombin time and prolongation in the prothrombin time. Neurological symptoms were assessed by electroencephalogram and CT brain, resulted negative, while a brain MRI revealed acute-subacute ischemic stroke. Based on these findings we suspected a diagnosis of TTP, subsequently confirmed by reduced activity of ADAMTS-13 with borderline ADAMTS-13 inhibitory antibodies. Immunological testing confirmed positivity of antiphospholipid antibodies and antinuclear antibodies.ResultsAccording to the last guidelines3 about management of acute episode of TTP, immediate therapy with high-dose corticosteroids (prednisone 1 mg/kg) and plasmapheresis was started and then we added infusion of rituximab (375 mg/m2/week for 4 times). Efficacy of treatment was evaluated by weekly dosage of ADAMTS13 activity, with a gradual rise in values (3 → 78%) and improvement in symptoms and laboratory examination. After persistent remission, we gradually reduced steroid therapy. Few months later, in February 2021, patient developed a bilateral comunitary pneumonia, that required hospitalization, oxygen - therapy (also with C-PAP) and endovenous antibiotics. After two weeks patient was discharged from hospital in good clinical health and he was subjected to periodic outpatients visits. Disease activity was in remission, so steroid therapy was reduced and recently we added hydroxychloroquine for APS. Some days ago patient developed covid – 19 infection, despite vaccination, and he was treated with monoclonal antibodies, with good clinical response.ConclusionWe have described a rare clinical case of TTP, despite concomitant warfarin treatment for primary anti-phospholipid syndrome. A careful follow-up of these medical conditions is recommended for patient’s fragility and for the risk of related serious clinical complications.

European Renal Best Practice endorsement of guidelines for diagnosis and therapy of thrombotic thrombocytopaenic purpura published by the International Society on Thrombosis and Haemostasis.

ABSTRACTThrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that is caused by severe ADAMTS-13 deficiency. Immune-mediated TTP develops due to autoantibodies against ADAMTS-13, whereas congenital TTP is caused by mutations in the ADAMTS13 gene. Diagnostic possibilities and treatment options in TTP have emerged in recent years, which prompted the International Society on Thrombosis and Haemostasis (ISTH) to publish clinical practice guidelines for the diagnosis and treatment of TTP in 2020. In this article, the European Renal Best Practice Working Group endorsed the ISTH guidelines and emphasizes a number of considerations, including the importance of rapid ADAMTS-13 activity testing, the use of rituximab and anti-von Willebrand factor therapies such as caplacizumab, that enhance the clinical applicability of the guidelines in Europe.

Cost-effectiveness of thrombotic thrombocytopenic purpura diagnosis: a retrospective analysis in the University Hospital Center of Lyon (France).

The aim of the present study was to perform an economic evaluation of two alternative assays of ADAMTS13 activity (A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats, member 13) for diagnosing thrombotic thrombocytopenic purpura (TTP) in the Hospital of Lyon (France). The study approach was more economic than clinical. We retrospectively calculated the prescription costs of ADAMST13 activity from January to December 2019 for patients depending on the assay: manual ELISA (Technozym) or automated assay (AcuStar Werfen, Instrumentation Laboratory). Then, we compared the cost of therapeutic plasma exchange (TPE) consumption awaiting ADAMTS13 activity assay results. From an economic point of view, the automated assay was more cost-effective. From a clinical one, we supposed that the faster results given by AcuStar could improve patient care by reducing the number of TPEs. Automated assay could improve patient care without increasing costs in our institution.

Indicators Differentiating Thrombotic Thrombocytopenic Purpura From Other Thrombotic Microangiopathies in a Canadian Apheresis Referral Center.

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy (TMA) caused by ADAMTS13 deficiency with mortality of up to 90% in the absence of treatment, typically therapeutic plasma exchange (TPE). TTP presents similarly to other TMAs in which TPE is ineffective and associated with morbidity and additional costs. Thus, we sought to assess clinical and laboratory parameters differentiating TTP from other TMAs in our institution's catchment population. We reviewed 8 years of data from a Canadian provincial apheresis center, including 100 patients with suspected TMA who underwent ADAMTS13 testing, 35 of whom were diagnosed with TTP. We assessed clinical and laboratory parameters to identify discriminators of TTP and assigned PLASMIC TTP prediction scores. We observed a higher frequency of neurologic symptoms, more severe thrombocytopenia, and less creatinine elevation in TTP relative to other TMAs. High PLASMIC scores (6-7 points) had 83% sensitivity and 88% specificity for TTP diagnoses; however, ADAMTS13 activity testing was required for correct diagnoses in 14 cases. Clinical and laboratory parameters including PLASMIC scoring may lead to misdiagnosis in some cases of TMA. ADAMST13 activity testing provides definitive diagnosis of TTP, supporting the role of rapid turnaround ADAMTS13 testing for appropriate treatment of TMAs.

Diagnosis and follow‐up of thrombotic thrombocytopenic purpura with an automated chemiluminescent ADAMTS13 activity immunoassay

BackgroundThrombotic thrombocytopenic purpura (TTP) is a life‐threatening thrombotic microangiopathy (TMA) caused by a severe functional deficiency in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats‐13), the specific von Willebrand factor (VWF) cleaving protease. ADAMTS13 activity is essential to diagnose TTP but remains challenging to assess, as reference ADAMTS13 activity assays are manual and time consuming. Current techniques also lack robustness in low detectable ADAMTS13 activity range, which could prove problematic for therapy‐driven monitoring. ObjectivesThe HemosIL AcuStar ADAMTS13 activity assay is a fast, automated chemiluminescent assay, the performance of which remains to be evaluated prospectively on very large cohorts of patients with TMA and in real‐life conditions. Patients and MethodsOur study was conducted over two successive sequences: a retrospective evaluation followed by a “real‐life” prospective evaluation. Overall, we evaluated the HemosIL AcuStar ADAMTS13 activity assay on 539 citrated plasma samples. We extensively studied linearity, limit of detection, contamination, intra‐assay and interassay precisions with a specific focus on levels < 25 IU/dL. Diagnostic performances for the detection of < 10 IU/dL ADAMTS13 activity and overall method comparison were conducted with the fluorescence resonance energy transfer (FRETS)‐VWF73 assay as the reference method. ResultsTechnical performance proved excellent. Robustness in low detectable ADAMTS13 activity range was good, potentially qualifying this assay for therapy‐driven monitoring. Comparison with the FRETS‐VWF73 assay was satisfactory (r2 = .83, P < .0001) as were the diagnostic performances for acute‐phase TTP (specificity, 99.7%; positive predictive value, 99.2%). ConclusionThe HemosIL AcuStar ADAMTS13 activity assay is a fast, reliable, automated technique well adapted as a first‐line ADAMTS13 activity assay for TTP diagnosis and follow‐up.

Sjögren's Syndrome Associated With Thrombotic Thrombocytopenic Purpura: A Case-Based Review.

ObjectiveTo review all published cases of the rare association between thrombotic thrombocytopenic purpura (TTP) and Sjögren's syndrome (SS). The authors report an additional case of this unique association.MethodsSystematic review of the literature and a case report. The database were articles published in PubMed/MEDLINE, Web of Science, LILACS, and SciELO, registered from 1966 to August 2020. The DESH terms were "Sjögren's syndrome" and "thrombotic thrombocytopenic purpura," without language limitation.ResultsMost patients were female (88%), and the age varied from 30 to 75 years old. Concerning the sequence of disease appearance, SS followed by TTP was seen in seven articles, TTP and SS in three, and simultaneous appearance of both diseases in three studies. Primary SS was observed in 16 patients, and secondary SS was detected in two cases: dermatomyositis and rheumatoid arthritis. Anemia was the most common TTP manifestation, followed by thrombocytopenia, fever, consciousness alteration, renal impairment, and schistocytes' appearance on a blood smear. Treatment involved plasmapheresis, plasma exchange, rituximab, glucocorticoid, and cyclophosphamide. A good outcome was noted in most studies; few patients died.ConclusionsTTP is a rare manifestation associated with SS. After the TTP diagnosis, plasmapheresis and/or plasma exchange should be immediately implemented.

Thrombocytopenic purpura on an organic farm with pen mating: a case report on the re-emergence of an old disease

BackgroundThrombocytopenia is an immune-mediated disease, which affects suckling piglets. Piglets are pale and inactive, show multiple hemorrhages and often die within days. Pathological examination reveals severe haemorrhages and oedema in several organs. Severe thrombocytopenia and elongated bleeding time characterize the disease haematologically.The sow produces antibodies against the thrombocyte antigens of the boar, which are present in the blood of the piglets. These isoimmune antibodies attack the platelets and megakaryocytes of the piglets, causing thrombocytopenia in succeeding matings of the same boar and sow. There is no known therapy against this condition. In the last few decades, the disease has become rare due to the increase of artificial insemination.Case presentationOn an organic breeding farm in Switzerland with a high percentage of natural pen matings, piglets of three litters showed haemorrhages on the skin, prolonged bleeding time and were generally in a reduced general state. A pathological examination revealed multifocal haemorrhages in the stomach, kidneys, dermis, mesenterium and spinal cord. Haematology showed a massive thrombocytopenia and regenerative anaemia. Due to these findings the diagnosis of thrombocytopenic purpura was established.To avoid further matings of the same boar and sow and thus more affected piglets, out of three possible boars the responsible sire had to be determined. This was achieved through array genotyping and subsequent computation of identity by descent and calculation of Mendelian errors for parentage verification. Thereby the responsible boar was identified and as a consequence removed from the farm. Further preventive measures, that had been established, included the recording of all matings and regular exchange of boars.ConclusionThe decreased number of natural matings with the surge of artificial insemination has probably reduced the number of cases of thrombocytopenic purpura and thus the disease awareness of farmers and veterinarians. However, as consumers wish for better animal welfare and higher ecological standards we may see a rise in natural matings and thus a return of the disease. In case of affected litters, genetic testing was proven a valid method for investigation and prevention of more cases and may be used more in the future.

Insights into ADAMTS13 structure: impact on thrombotic thrombocytopenic purpura diagnosis and management.

Fundamental knowledge on the role of a disintegrin and metalloprotease with thrombospondin type one repeats, member 13 (ADAMTS13) has been crucial to better understand the pathophysiology of the rare and life-threatening disease thrombotic thrombocytopenic purpura (TTP). ADAMTS13 works through a molecular zipper mechanism to proteolyze its substrate von Willebrand factor (VWF). Recent insights into the structure and function of ADAMTS13 led to the identification of an allosteric activation mechanism. Therefore, ADAMTS13 is roughly folded in two in which the N-terminal spacer (S) domain and C-terminal T7-CUB2 domains interact to adopt a closed conformation. Upon substrate binding, ADAMTS13 adopts an open conformation in which the S-T7-CUB2 interaction is abrogated to further position VWF towards the catalytic cleft, inducing activation of the latent metalloprotease domain and resulting in cleavage of VWF. Unravelling the structure function relationship of ADAMTS13 helped identifying open ADAMTS13 as a novel and unique biomarker for immune-mediated TTP (iTTP). This novel biomarker has potential in the diagnosis, treatment and follow-up of iTTP. In this review, the most recent findings on the structure and working mechanism of ADAMTS13 are addressed. In addition, how those findings led to the identification of a novel biomarker, and how this novel biomarker could have an impact on the diagnosis, management and follow-up of iTTP patients are discussed.

P0137FIRST RUSSIAN BOSIMILAR OF ECULIZUMAB IN THE TREATMENT OF AN ADULT PATIENT WITH ATYPICAL HEMOLYTIC UREMIC SYNDROME

Abstract Background and Aims The disease diagnostics results and the efficacy of pathogenetic treatment when transferring from the original drug to the biosimilar were evaluated during clinical observation of an adult patient with aHUS. Method A 46-year-old patient has a history of hypertension since 2012 and maximum ABP of 230/130 mmHg. In 2016, newly diagnosed azotemia was identified (blood creatinine — 140 μmol/L, GFR by EPI — 54 mL/min/1.73m2). In 2018, the patient suffered an acute cerebrovascular accident in the vertebrobasilar area. On admission to Almazov National Medical Research Centre, blood test showed: creatinine – 260 μmol/L (GFR by EPI — 28 mL/min/1.73m2), urea – 11.52 mmol/L, LDH – 130 U/L, complement system C3 – 1.32 g/L, С4 – 0.37 g/L, hemoglobin – 144 g/L, platelets – 302*109/L; urinalysis showed: daily protein loss – 2.6 g/day, RBC – 0–1 per field. Taking into account the kidney damage, the renal fine-needle aspiration biopsy was performed, revealing histopathological findings typical of chronic thrombotic microangiopathy of extreme severity, arteriolar arteriosclerosis with total or subtotal luminal occlusion, extensive secondary perihilar segmental glomerulosclerosis (27%); and global glomerulosclerosis (55%). According to the study results, the secondary genesis of TMA was ruled out, as well as STEC-HUS and thrombotic thrombocytopenic purpura (TTP), systemic diseases (systemic lupus erythematosus, antiphospholipid syndrome (APS), scleroderma), malignancies, HIV infection, sepsis, malignant arterial hypertension, adverse drug events, or disseminated intravascular coagulation (DIC). Plasma ADAMTS-13 levels were also assessed. Its activity was 64% (normal range 93–113%) of ADAMTS-13 activity in the control plasma, thus the diagnosis of thrombocytopenic purpura was ruled out. Due to the absence of anti-CFH-antibodies the antibody origin of aHUS was also ruled out. To assess the contribution of additional factors promoting the development of TMA, the polymorphism of hemostasis genes was studied to reveal homozygous genotypes of platelet collagen receptors (ITGA2: 807 С/Е), heterozygous genotypes of fibrinogen genes (FGB: 455 G/А), folate cycle enzymes (methylenetetrahydrofolate reductase (MTHFR: 677 C/T), methionine synthase (MTR: 2756 A/G (D919G)), responsible for a pronounced tendency towards hyperhomocysteinemia. In the clinical case the diagnosis of aHUS was obvious, which was supported by the classical symptom cluster of TMA and histopathological verification in the absence of data suggestive of other pathological conditions. The peculiarity of this clinical case is the late diagnosis, long-standing course, and severity (complications such as an acute cerebrovascular accident in the vertebrobasilar area, target lesions, kidneys in particular). Results Taking into account the primary diagnosis, treatment with a standard dose of eculizumab was initiated. After three months of treatment the patient was transferred to therapy with Russian biosimilar of eculizumab. After the switch from the original drug, the therapy with eculizumab biosimilar continued to be associated with a positive trend including a gradual decline in azotemia level (blood creatinine – 115 μmol/L (GFR by EPI – 52 mL/min/1.73m2), blood urea – 7.10 mmol/L), proteinuria (daily protein loss – 0.6 g/day). The comprehensive treatment including antihypertensive therapy also led to the normalisation of ABP values. No adverse events associated with the therapy were noted. Conclusion The obtained results demonstrate high efficacy and safety of eculizumab biosimilar in the treatment of the adult patient with aHUS.

Vasculitis leucocitoclástica asociada a medicamentos

Introduction. Leukocytoclastic vasculitis (LV) is the presence of leukocytoclasis (fragmentation of the nuclei of neutrophils or "nuclear dust") in the wall of small vessels and around them. Case Presentation. A 37-yearold female patient with a diagnosis of thrombocytopenic purpura who starts treatment with ceftazidime and phenytoin, which causes LV. Conclusions. The case presented is associated with pharmacological etiology because the patient does not present a concomitant etiological condition.

Plasmic score applicability for the diagnosis of thrombotic microangiopathy associated with ADAMTS13-acquired deficiency in a developing country

BackgroundThrombotic thrombocytopenic purpura (TTP) is a potentially fatal disease that requires early diagnosis and treatment that can be made possible by applying the PLASMIC score. This study aims to evaluate this score applicability for patients with suspected TTP in a developing country. MethodsThis was a retrospective study performed at a tertiary hospital in the northeastern region of Brazil. Patients were analyzed in two groups: ADAMTS13 activity <10% and activity >10%. Patients were stratified according to the PLASMIC score, and the level of agreement between the PLASMIC score and the ADAMTS13 activity was evaluated. ResultsEight patients with thrombotic microangiopathy were included. Four patients had ADAMTS13 activity <10%, all with a PLASMIC score =6. The other four had ADAMTS13 activity >10%, all with a score <6. Based on a score =6 for presumptive diagnosis of TTP, we attained a 100% diagnostic accuracy in our sample. The PLASMIC score was also able to accurately predict response to plasma exchange and the risk of long-term unfavorable outcomes. ConclusionsThe reproducibility of the PLASMIC score was quite satisfactory in our sample. It accurately discriminates between patients who had ADAMTS13 deficiency and those with normal enzyme activity, precluding the need for specific laboratory evaluation, which is not always available. This score can be useful for an early diagnosis and indicates which patients will benefit from the treatment in developing countries.

Validation of the PLASMIC score, a clinical prediction tool for thrombotic thrombocytopenic purpura diagnosis, in Chinese patients

BackgroundThe recently published PLASMIC score was shown to be an excellent diagnostic model to identify patients with severe ADAMTS-13 deficiency. However, it is unclear if this score is suitable for Chinese patients with suspected thrombotic thrombocytopenic purpura (TTP). MethodsWe retrospectively studied a Chinese cohort of 134 consecutively hospitalized patients with thrombotic microangiopathy, ADAMTS-13 test results, and clinical information between January 2015 and June 2018, the PLASMIC score's distinguishing ability in this cohort was evaluated. We also combined the lactate dehydrogenase (LDH)-to-aspartate aminotransferase (AST) ratio with the PLASMIC score to determine its predictive value for TTP in pregnancy. ResultsIn this Chinese cohort, 39 patients were diagnosed with TTP using ADAMTS13 testing. When stratified at high (score, 6–7) vs. low–intermediate (score, 0–5) risk, the PLASMIC test predicted TTP with a positive predictive value of 51%, negative predictive value of 92%, sensitivity of 85%, and specificity of 58%. In pregnant patients, a combination of the PLASMIC score of 6–7 and LDH-to-AST ratio of ≥5.5 showed a higher positive predictive value for TTP compared with the PLASMIC score alone (71% vs. 35%, P < 0.001). Removing the component MCV < 90 fL from the PLASMIC score did not reduce its distinguishing power, as measured using the C statistic (0.837, 95%CI 0.767–0.907 vs. 0.797, 95%CI 0.718–0.877; P = 0.771). ConclusionsCombination with a higher LDH-to-AST ratio improves the positive predictive value of the PLASMIC score in pregnant patients. A simpler score without MCV < 90 fL can be used to identify TTP in Chinese patients.

Thrombotic thrombocytopenic purpura.

SummaryThrombotic thrombocytopenic purpura (TTP) is a clearly defined entity of the thrombotic microangiopathies (TMA), a heterogeneous group of disorders characterized by microangiopathic hemolytic anemia with red cell fragmentation, thrombocytopenia and organ dysfunction due to disturbed microcirculation. TTP is characterized by a severe deficiency of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), an enzyme responsible for physiological cleavage of von Willebrand factor (VWF). Organ dysfunction can be severe and life-threatening, and immediate start of appropriate therapy is necessary to avoid permanent damage or death. Until recently, therapeutic options were limited to symptomatic measures, which were not standardized or based on high scientific evidence. In recent years, not only considerable progress has been made in better diagnosis of TTP, but also new therapeutic strategies have been established. Initial treatment is still based on plasma exchange and symptomatic measures to protect organ function, but new concepts (immunosuppression, targeted anti-VWF or anti-complement therapy, replacement with recombinant enzymes) have recently demonstrated impressive advantages.