ADAMTS13 Deficiency Research Articles

Validation of PLASMIC score in a cohort of patients with suspected thrombotic microangiopathy in an academic medical centre.

The PLASMIC score is a rapid and inexpensive clinical assessment tool for predicting severe ADAMTS13 deficiency (<10% activity) in patients with suspected thrombotic thrombocytopenic purpura (TTP). The score includes 7 parameters: absence of active cancer, patient not having received stem cell transplant or organ transplant, platelet count <30×109/L, haemolysis, mean corpuscular volume <90 fl, International Normalized Ratio <1.5, and serum creatinine <2 mg/dL. In this retrospective study, we evaluated a cohort of 59 consecutive patients with suspected thrombotic microangiopathy who had been referred to the Hemostasis and Thrombosis Center of the "Federico II" University of Naples, Italy, for measurement of ADAMTS13 activity. Relevant clinical and laboratory information were collected for all patients. The PLASMIC score was calculated in 52 of the 59 patients included in the study. In the high-risk group (PLASMIC score 6 or 7), 12 out of 20 patients (60%) had ADAMTS13 <10%. Interestingly, all 6 patients (100%) with PLASMIC score 7 had ADAMTS13 <5%. In the intermediate risk group (score 5), only one case out of 17 (5.9%) had ADAMTS 13 <10%. In the low-risk group (score 0-4), none of the patients had severe ADAMTS13 deficiency. The collected data enabled the sensitivity and specificity of PLASMIC score in TTP to be calculated, achieving 92% (95% CI: 0.80-0.98) and 79% (95% CI: 0.66-0.89), respectively. The PLASMIC score was seen to be a very efficient tool in distinguishing between patients with severe ADAMTS13 deficiency from those without, with an AUC of 0.92 (95% CI: 0.82-1.0; p<0.001). In our cohort, a high-risk PLASMIC score successfully predicted patients with severe ADAMTS13 deficiency, allowing the clinician to quickly define the best therapeutic approach, especially useful for those clinicians not used to the diagnosis and treatment of thrombotic microangiopathies.

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V.

The vascular endothelium has several important functions, including hemostasis. The homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins and between fibrinolytic and antifibrinolytic ones. Coagulopathies are characterized by a mutation-induced alteration of the function of certain coagulation factors or by a disturbed balance between the mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement and nonreplacement treatments or in the administration of antifibrinolytic agents. Rebalancing products reestablish hemostasis by inhibiting natural anticoagulant pathways. These agents include monoclonal antibodies, such as concizumab and marstacimab, which target the tissue factor pathway inhibitor; interfering RNA therapies, such as fitusiran, which targets antithrombin III; and protease inhibitors, such as serpinPC, which targets active protein C. In cases of thrombophilia (deficiency of protein C, protein S, or factor V Leiden), treatment may consist in direct oral anticoagulants, replacement therapy (plasma or recombinant ADAMTS13) in cases of a congenital deficiency of ADAMTS13, or immunomodulators (prednisone) if the thrombophilia is autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) is used in the context of severe thrombophilia, regardless of the cause of the disorder. In cases of disseminated intravascular coagulation, the treatment of choice consists in administration of antifibrinolytics, all-trans-retinoic acid, and recombinant soluble human thrombomodulin.

Lombardy diagnostic and therapeutic network of thrombotic microangiopathy

BackgroundThrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy (TMA) requiring urgent treatment. Standardization of its diagnosis and optimal management is challenging. This study aimed to evaluate the role of centralized, rapid testing of ADAMTS13 in patients experiencing acute TMAs requiring plasma-exchange (PEX) and to estimate the incidence of TTP in a large Italian Region.MethodsWe perfomed a cohort study in the frame of the project “Set-up of a Lombardy network for the study and treatment of patients undergoing apheresis”, including 11 transfusion centers in the Region. Consecutive patients referred from 2014 to 2016 with acute TMAs requiring PEX were enrolled. Centralized ADAMTS13 activity testing was performed at the Milan Hemophilia and Thrombosis Center within 24 h.ResultsForty-three TMA patients (44 events) were enrolled, of whom 35 (81%) had severe ADAMTS13 deficiency. Patients with severe ADAMTS13 deficiency were younger, mainly women, with a higher prevalence of autoimmune disorders and a lower prevalence of cancer. Clinical and laboratory characteristics of patients with and without severe ADAMTS13 deficiency largely overlapped, with a lower platelet count being the only baseline marker that significantly differed between the two patient groups (ADAMTS13 activity < 10% vs ≥ 10%: median difference of -27 × 109/l, 95% CI − 37 to − 3). PEX treatment was initiated in all patients, but soon discontinued in cases without severe ADAMTS13 deficiency. In this group, the mortality rate was higher and no episode exacerbations or relapses within 6 months occured. The estimated average annual incidence of acute acquired TTP events was 1.17 [0.78–1.55] per million people.ConclusionsSevere ADAMTS13 deficiency distinguished two groups of patients with largely overlapping clinical features but different treatment and disease course. This study provides a feasible model implemented in a large Italian region for the practical clinical approach to TMAs and underlines the importance of urgent ADAMTS13 activity testing for an accurate differential diagnosis and therapeutic approach.

PB2304: THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP): A SINGLE-CENTER EXPERIENCE

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, consumption thrombocytopenia, and organ injury. TTP pathophysiology is based on a severe ADAMTS13 deficiency, the specific von Willebrand factor (VWF)-cleaving protease. Aims: In this study, we aim to report our experience in patients with TTP, identify the main clinical and laboratory disease findings, treatment patterns, and evolution in these patients. Methods: This is a retrospective study of all adult patients (> 15 years) diagnosed and treated between 2000 and 2021 with TTP, at the hematology department of the university hospital of Sfax, Tunisia. Results: A total of 11 patients were enrolled in this study period. The median age was 38 years [range 22-72] and there was a female preponderance (2.6). At presentation, the majority of patients (8/11) had asthenia and neurological symptoms: confusion in 4 cases, convulsive seizure in 2 cases, and cerebrovascular accident in 2 cases. Five patients had fever, 4 had jaundice, and 3 presented with bleeding. Microangiopathic hemolytic anemia was noted in all patients with mean hemoglobin of 7.3 g/dl [5-8 g/dL], and 5% to 20% of schistocytes. Thrombocytopenia with platelets < 100x109/l occurred in 10 of 11 patients with mean platelet of 14 x109/l. Three patients had high serum creatinine levels, proteinuria and hematuria were present in 3 and 2 other cases respectively. The causal investigation showed that TTP was related to viral infection in 3 cases, newly discovered neoplasia in 2 cases, pregnancy in 3 cases, an immunologic disorder in one case, and idiopathic in 2 cases. Of the 3 pregnancy cases, 2 had a plasma activity of ADAMTS13 lower than 5%, and TTP was thus related to Upshaw-Schulman syndrome. For treatment, plasmapheresis associated with corticosteroids was promptly started in 9 patients, and 2 patients received corticosteroids alone due to hemodynamic instability. Four patients had also Rituximab as salvage therapy, and for the 2 patients with neoplasia, adequate chemotherapy was initiated. Four patients died due to shock with neurological involvement, respiratory failure, or multiple organic failure. The other 7 patients achieved remission, but two of them relapsed. Summary/Conclusion: Our study is consistent with clinical trial findings reported in the literature, showing that TTP has heterogeneous modes of presentation and not all patients have the complete typical features present. Since it has a fatal outcome, rapid diagnosis and management are recommended. Finally, the causal diagnosis should be made to initiate the appropriate curative treatment.

Effect of Blood Groups on Clinical Presentations and Treatment Outcomes in Immune Thrombotic Thrombocytopenic Purpura Patients with Severe ADAMTS13 Deficiency: A Multi-Center Experience

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by accumulation of ultra-large von Willebrand factor (vWF) due to the significantly reduced activity ADAMTS13. Limited studies have been published examining the blood group as an epidemiological factor that can contribute to development of TTP. It has been suggested that due to low vWF levels, the distribution of the “O” blood group among TTP patients may be lower than anticipated compared to the blood group distribution rates in the normal population. The aim of this study was to explore the relationship between blood groups and the clinical outcome of immune TTP (iTTP). Methods: Thirty patients with iTTP with severe ADAMTS13 deficiency were enrolled. Data collection commenced in January 2011 and was completed by June 2020. It was analyzed whether there was a difference between the blood groups in terms of frequency of iTTP, response to treatment, frequency of relapse, and clinical and laboratory results. Results and Conclusions: The distribution of group “A” among patients with iTTP was higher than expected. Although not statistically significant, patients with blood group “O” required more TPE for the treatment and relapse rate was statistically higher than other blood groups. Mortality rate in all patients was 6.7%. Although blood group “A” is a risk factor for iTTP, the frequency of relapse is higher in the blood group “O.”

How I treat immune-mediated thrombotic thrombocytopenic purpura after hospital discharge

AbstractImmune-mediated thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy characterized by an acquired ADAMTS13 deficiency as a result of the presence of an antibody inhibitor of ADAMTS13 leading to the formation of ultralarge von Willebrand multimers. Treatment of iTTP includes plasma exchange, high-dose glucocorticoids, rituximab, and, more recently, caplacizumab, to prevent the development of exacerbations. There is the risk of both relapse and long-term complications that include neurocognitive deficits and cardiovascular events that occur in patients in remission after recovery from an acute iTTP episode. Data on the risk factors for the development of these complications, the appropriate screening, and treatment are limited due to the paucity of research. This article is a review of the current understanding on the risk factors for exacerbation, relapse, and long-term complications of iTTP and discusses an approach to observing patients with iTTP after hospital discharge and during the long-term follow-up in the outpatient setting.

POS-035 A PHASE 3 STUDY TO SUPPORT IPTACOPAN REGISTRATION IN ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS): OVERVIEW OF APPELHUS STUDY DESIGN CONSIDERATIONS

POS-035 A PHASE 3 STUDY TO SUPPORT IPTACOPAN REGISTRATION IN ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS): OVERVIEW OF APPELHUS STUDY DESIGN CONSIDERATIONS

POS-001 A NOVEL CFHR5 COPY NUMBER VARIATION ASSOCIATED WITH POST-PARTUM ATYPICAL HUS SUPERIMPOSED TO HELLP SYNDROME

Pregnancy and postpartum are triggers for various forms of thrombotic microangiopathy (TMA), a lesion characterized by endothelial injury and thrombosis in the microcirculation of various organs. These forms include thrombotic thrombocytopenic purpura (TTP), caused by ADAMTS13 deficiency, and atypical hemolytic uremic syndrome (aHUS), most often associated with genetically determined dysregulation of complement system. HUS is the most common form of TMA in the post-partum period. The diagnosis of pregnancy-associated HUS can be difficult because preeclampsia and HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome may present with clinical and laboratory features of TMA that however commonly resolve spontaneously after delivery.Here, we report the biochemical and genetic characterization of a 22 years old primigravida of African origin who presented at 38 weeks of gestation with severe hypertension, nephrotic syndrome (NS) and elevated liver enzymes, consistent with a diagnosis of HELLP.

POS-039 ATYPICAL RENAL RECOVERY FROM ATYPICAL HEMOLYTIC UREMIC SYNDROME

Atypical hemolytic uremic syndrome (aHUS) is a rare disease, caused by dysregulation of the alternative complement pathway, characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal insufficiency, in the absence of positive Shiga toxin or ADAMTS13 deficiency. First line treatment is eculizumab, that allows for, in most of cases, a complete remission within six months. We present the case of an atypical late renal response to eculizumab administration.

Naturally Occurring Anti-Idiotypic Antibodies Portray a Largely Private Repertoire in Immune-Mediated Thrombotic Thrombocytopenic Purpura.

Rare immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening disease resulting from a severe autoantibody-mediated ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13) deficiency. Acute iTTP episodes are medical emergencies, but when treated appropriately &amp;gt;95% of patients survive. However, at least half of survivors will eventually experience a relapse. How remission of an initial episode is achieved and factors contributing to reemergence of anti-ADAMTS13 Abs and a relapsing course are poorly understood. In acquired hemophilia and systemic lupus erythematosus, anti-idiotypic Abs counteracting and neutralizing pathogenic autoantibodies contribute to remission. We selected and amplified the splenic anti-idiotypic IgG&lt;sub&gt;1&lt;/sub&gt; Fab κ/λ repertoire of two relapsing iTTP patients on previously generated monoclonal inhibitory anti-ADAMTS13 Fabs by phage display to explore whether anti-idiotypic Abs have a role in iTTP. We obtained 27 single anti-idiotypic Fab clones, half of which had unique sequences, although both patients shared four H chain V region genes (V&lt;sub&gt;H&lt;/sub&gt;1-69*01, V&lt;sub&gt;H&lt;/sub&gt;3-15*01, V&lt;sub&gt;H&lt;/sub&gt;3-23*01, and V&lt;sub&gt;H&lt;/sub&gt;3-49*03). Anti-idiotypic Fab pools of both patients fully neutralized the inhibitor capacity of the monoclonal anti-ADAMTS13 Abs used for their selection. Preincubation of plasma samples of 22 unrelated iTTP patients stratified according to functional ADAMTS13 inhibitor titers (&amp;gt;2 Bethesda units/ml, or 1-2 Bethesda units/ml), with anti-idiotypic Fab pools neutralized functional ADAMTS13 inhibitors and restored ADAMTS13 activity in 18-45% of those cases. Taken together, we present evidence for the presence of an anti-idiotypic immune response in iTTP patients. The interindividual generalizability of this response is limited despite relatively uniform pathogenic anti-ADAMTS13 Abs recognizing a dominant epitope in the ADAMTS13 spacer domain.

Comparison of absolute immature platelet count to the PLASMIC score at presentation in predicting ADAMTS13 deficiency in suspected thrombotic thrombocytopenic purpura

IntroductionThrombotic thrombocytopenic purpura (TTP) demands rapid initiation of therapeutic plasma exchange to avoid severe complications associated with it. ADAMTS13 activity <10% defines TTP, however, this is a send-out test at most institutions. We have previously reported our experience looking at absolute immature platelet counts (A-IPC) in TTP patients. Thus, we compared A-IPC on admission to the PLASMIC score to predict ADAMTS13 deficiency. Materials and methodsOf seventy-two patients identified, 52 met inclusion criteria. All patients were suspected of new-onset TTP and had A-IPC on admission. Of these patients, 25/52 were later shown to have ADAMTS13 <10%, defined as TTP group, and 27/52 had ADAMTS13 >10% and are henceforth classified as non-TTP. ResultsPatients with TTP were found to have A-IPC below reference range (<1.5 × 109/L) and responded to therapy as shown by fold-increases in A-IPC (p < 0.0001), neither seen in non-TTP patients. A-IPC had a significant correlation with ADAMTS13 deficiency (p = 0.0001) with high sensitivity, specificity, positive and negative predictive values. Comparison of A-IPC to PLASMIC score indicated that the former identified all TTP patients compared to PLASMIC score even in patients obtaining scores of 4 and 5. Finally, Receiver Operating Characteristic curves showed A-IPC had area under the curve of 0.986. ConclusionsA-IPC below reference range and A-IPC fold-increases were only observed in TTP patients. There was strong association between A-IPC and ADAMTS13 deficiency and A-IPC predicted patients with ADAMTS13 deficiency. Future larger studies are needed to determine ways to apply findings in suspected TTP patients.

Application of PLASMIC Score in Risk Prediction of Thrombotic Thrombocytopenic Purpura: Real-World Experience From a Tertiary Medical Center in Taiwan.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder caused by severe ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) deficiency (activity <10%). Urgent intervention based on the timely evaluation of ADAMTS13 level is crucial to guide optimal therapy. The recently developed PLASMIC score based on seven items allows the rapid identification of patients at high risk for TTP due to severe ADAMTS13 deficiency. This retrospective study included 31 hospitalized patients with suspicious thrombotic microangiopathy in National Cheng Kung University Hospital from December 2016 to July 2021. Data on ADAMTS13 activity and medical and laboratory information were retrieved from medical records. The PLASMIC score could be calculated in 24 of the 31 patients with available data, and the final cohort was stratified according to the 7-point PLASMIC score. All patients with high PLASMIC score (6–7) exhibited severe ADAMTS13 deficiency (activity ≤10%). One patient with a brain tumor and a PLASMIC score of 6 did not have severe ADAMTS13 activity of ≤10%. The patients in the intermediate- and low risk groups (PLASMIC scores of 5 and 0–4, respectively) exhibited ADAMTS13 activities of above 10%. Given the role of prompt diagnosis in the timely delivery of appropriate therapy, these findings confirm and strengthen the predictive value of the PLASMIC score in patients at high risk for TTP due to severe ADAMTS13 deficiency.

Recent advances in the management of immune-mediated thrombotic thrombocytopenic purpura.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially life-threatening thrombotic microangiopathy caused by autoantibody-mediated severe ADAMTS13 deficiency. TTP should be suspected in patients with microangiopathic hemolytic anemia and thrombocytopenia without a definite cause. Early detection of iTTP and prompt treatment with plasma exchange and corticosteroids are essential. Rituximab administration should be considered for refractory or relapsed iTTP, and can be used as a first-line adjuvant or preemptive therapy. Treatment with caplacizumab, a novel anti-von Willebrand factor nanobody, resulted in a faster time to platelet count response, significant reduction in iTTP-related deaths, and reduced incidence of refractory iTTP. TTP survivors showed a higher rate of chronic morbidities, including cardiovascular disease and neurocognitive impairment, which can lead to a poor quality of life and higher mortality rate. Meticulous long-term follow-up of TTP survivors is crucial.

Beneficial effect of fresh frozen plasma in reducing renal complications in Hemiscorpius lepturus scorpion envenomated children with severe hemoglobinuria: an open label randomized clinical trial

Acute kidney injury is a common complication of Hemiscorpius lepturus (HL) scorpion envenomation, via several mechanisms including pigment nephropathy, direct nephrotoxic effects of scorpion venom, hemolytic uremic syndrome (HUS), and acute interstitial nephritis. ADAMTS13 deficiency is highly prevalent in patients with severe HL scorpion envenomation and is effective in the development of HUS. Fresh frozen plasma (FFP), by replacing ADAMTS13, has proven effects on HL scorpion envenomated patients with HUS. This study evaluated the role of FFP in reducing of kidney injuries in complicated cases. In this open label randomized clinical trial, a total of 98 patients with massive hemoglobinuria following HL scorpion envenomation were included in the intervention and control groups (49 patients per group). The intervention group received FFP (10 cc/kg every 12 hours for three days) in addition to the anti-venom and other current therapies. Laboratory findings of renal activity, hemolysis, and urinalysis were evaluated in both groups, and maximum changes were compared. Comparison of maximum changes in laboratory findings between the two groups showed that administration of FFP can significantly reduce the deterioration of Blood Urea Nitrogen (BUN) and Creatinine (Cr) levels in the intervention group (p < 0.001 and p = 0.003, respectively). In comparison with the control group, the incidence of proteinuria was significantly lower (p = 0.012), reduction of platelet count was significantly less (p = 0.044), and increase of lactate dehydrogenase (LDH) and leukocytosis was lower in the intervention group (p = 0.037 and p = 0.007, respectively). The mean length of hospital stay was 5.44 days in the intervention group and 5.933 days in the control group (p = 0.149). According to the present findings, FFP can significantly reduce the development of kidney damage after HL scorpion envenomation and can be safely used against the fatal progression of venom complications in severe cases, along with other common treatments.

Thrombotic Thrombocytopenic Purpura (ADAMTS13 [a Disintegrin and Metalloproteinase With a Thrombospondin Type 1 Motif, Member 13] Deficiency) as Cause of Recurrent Multiterritory Ischemic Strokes.

Thrombotic Thrombocytopenic Purpura (ADAMTS13 [a Disintegrin and Metalloproteinase With a Thrombospondin Type 1 Motif, Member 13] Deficiency) as Cause of Recurrent Multiterritory Ischemic Strokes.

Impaired coagulation, liver dysfunction and COVID-19: Discovering an intriguing relationship.

Coronavirus disease 2019 (COVID-19) is, at present, one of the most relevant global health problems. In the literature hepatic alterations have been described in COVID-19 patients, and they are mainly represented by worsening of underlying chronic liver disease leading to hepatic decompensation and liver failure with higher mortality. Several potential mechanisms used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to cause liver damage have been hypothesized. COVID-19 primary liver injury is less common than secondary liver injury. Most of the available data demonstrate how liver damage in SARS-CoV-2 infection is likely due to systemic inflammation, and it is less likely mediated by a cytopathic effect directed on liver cells. Moreover, liver alterations could be caused by hypoxic injury and drugs (antibiotics and non-steroidal anti-inflammatory drugs, remdesivir, tocilizumab, tofacitinib and dexamethasone). SARS-CoV-2 infection can induce multiple vascular district atherothrombosis by affecting simultaneously cerebral, coronary and peripheral vascular beds. Data in the literature highlight how the virus triggers an exaggerated immune response, which added to the cytopathic effect of the virus can induce endothelial damage and a prothrombotic dysregulation of hemostasis. This leads to a higher incidence of symptomatic and confirmed venous thrombosis and of pulmonary embolisms, especially in central, lobar or segmental pulmonary arteries, in COVID-19. There are currently fewer data for arterial thrombosis, while myocardial injury was identified in 7%-17% of patients hospitalized with SARS-CoV-2 infection and 22%-31% in the intensive care unit setting. Available data also revealed a higher occurrence of stroke and more serious forms of peripheral arterial disease in COVID-19 patients. Hemostasis dysregulation is observed during the COVID-19 course. Lower platelet count, mildly increased prothrombin time and increased D-dimer are typical laboratory features of patients with severe SARS-CoV-2 infection, described as “COVID-19 associated coagulopathy.” These alterations are correlated to poor outcomes. Moreover, patients with severe SARS-CoV-2 infection are characterized by high levels of von Willebrand factor with subsequent ADAMTS13 deficiency and impaired fibrinolysis. Platelet hyperreactivity, hypercoagulability and hypofibrinolysis during SARS-CoV-2 infection induce a pathological state named as “immuno-thromboinflammation.” Finally, liver dysfunction and coagulopathy are often observed at the same time in patients with COVID-19. The hypothesis that liver dysfunction could be mediated by microvascular thrombosis has been supported by post-mortem findings and extensive vascular portal and sinusoidal thrombosis observation. Other evidence has shown a correlation between coagulation and liver damage in COVID-19, underlined by the transaminase association with coagulopathy, identified through laboratory markers such as prothrombin time, international normalized ratio, fibrinogen, D-dimer, fibrin/fibrinogen degradation products and platelet count. Other possible mechanisms like immunogenesis of COVID-19 damage or massive pericyte activation with consequent vessel wall fibrosis have been suggested.

Cerebral Infarction due to Severe ADAMTS-13 Deficiency with Normal Hematological Parameters: A Cause of Cryptogenic Stroke

ObjectivesThrombotic thrombocytopenic purpura (TTP) is a microangiopathy resulting from an inherited or acquired severe deficiency in a disintegrin and metalloproteinase called ADAMTS-13. Acquired or immune TTP is classically described as a pentad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fever, renal insufficiency and neurological symptoms. Thrombotic thrombocytopenic purpura has been linked to stroke with the presence of hematologic abnormalities but whether or not severe ADAMTS-13 deficiency can cause stroke without hematological abnormalities is unknown. Materials and MethodsAs part of routine clinical care, we identified four cases of recurrent stroke attributed to severe deficiency of ADAMTS-13. We also conducted a search of a centralized electronic health record database including all inpatients and outpatient charts at a single academic medical center over the last ten years in an attempt to identify additional cases. ResultsHere we present four cases of stroke and severe ADAMTS-13 deficiency where stroke episodes occurred without microangiopathic hemolytic anemia or severe thrombocytopenia. These cases show the need to consider severe ADAMTS-13 deficiency in the setting of recurrent cryptogenic stroke in young patients. Conclusions and RelevanceTTP directed therapies may be considered for patients with recurrent stroke who have extremely low ADAMTS-13 levels, even when platelet and hemoglobin values are normal.

THROMBOTIC THROMBOCYTOPENIC PURPURA AFTER VACCINATION AGAINST COVID-19 – A CASE REPORT

Thrombotic thrombocytopenic purpura (TTP) is a rare but fatal thrombotic microangiopathy. Circulating AntiADAMTS13 antibodies produced in response to various triggering events, such as vaccinations, autoimmune disorders, malignancy, and administration of several drugs lead to acquired TTP (aTTP). This case concerns a 26-year-old male with aTTP after receiving the second dose of the Covishield vaccine (Oxford-AstraZeneca COVID-19 vaccine, code-named AZD1222). He presented with bruises, petechia, fatigue, dyspnea, and arthralgia post-vaccination. Laboratory reports showed thrombocytopenia, hemolytic anemia, a significant ADAMTS13 deficiency, and a high level of autoantibody titer against ADAMTS13. We treated the patient with plasma exchange therapy and prednisolone, and after the treatment, he recovered.

Mind and matter: The neurological complications of thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially fatal condition, with >90% mortality if untreated; deficiency of ADAMTS13 leads to widespread microvascular thromboses and organ injury particularly affecting organs with high shear stress, including the brain. The acute neurological complications have historically been those most feared by clinicians and synonymous with a poor prognosis. TTP, however, is no longer perceived as two extremes of acute presentation and remission, rather once diagnosed a chronic condition with the potential for a long-term symptom burden. Optimal neuroimaging timing and modality lacks consensus and as we learn more about the changes seen during the acute and chronic stages of TTP, there is scope for neuroimaging to play a greater role in guiding management and the secondary prevention of vascular disease. Reduced ADAMTS13 activity levels have been associated with increased thrombotic risk and novel therapies including caplacizumab and recombinant ADAMTS13 may offer a neuroprotective role. Given the increasing evidence of the neurocognitive and psychological disease in TTP, the importance of screening and timely intervention should not be underestimated. As more patients are surviving their initial TTP presentation, it is crucial for us to develop a greater understanding of the longer-term morbidity affecting these patients.

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.