RESUMEN
Therapeutic options in immune-mediated thrombotic thrombocytopenic purpura (iTTP) during pregnancy are limited besides therapeutic plasma exchange (TPE) and corticosteroids. The report by Odetola et al. suggests that caplacizumab represents a reasonable option in iTTP during pregnancy, especially when the disease is not rapidly controlled with the standard TPE-corticosteroid association. Commentary on: Odetola et al. Safe and effective use of caplacizumab in pregnancy-related acquired thrombotic thrombocytopenic purpura. Br J Haematol 2023;202:879-882.
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Púrpura Trombocitopénica Trombótica , Anticuerpos de Dominio Único , Humanos , Embarazo , Femenino , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Factor de von Willebrand , Anticuerpos de Dominio Único/uso terapéutico , Corticoesteroides/uso terapéutico , Intercambio Plasmático , Proteína ADAMTS13RESUMEN
The 100th anniversary of the first description of Thrombotic Thrombocytopenic Purpura (TTP) as a disease by Dr. Eli Moschcowitz approaches. For many decades, TTP remained mostly a mysterious fatal condition, where diagnosis was often post-mortem. Initially a pentad of symptoms was identified, a pattern that later revealed to be fallible. Sporadic observations led to empiric interventions that allowed for the first impactful breakthrough in TTP treatment, almost 70 years after its first description: the introduction of plasma exchange and infusions as treatments. The main body of knowledge within the field was gathered in the latest three decades: patient registries were set and proved crucial for advancements; the general mechanisms of disease have been described; the diagnosis was refined; new treatments and biomarkers with improvements on prognosis and management were introduced. Further changes and improvements are expected in the upcoming decades. In this review, we provide a brief historic overview of TTP, as an illustrative example of the success of translational medicine enabling to rapidly shift from a management largely based on empiricism to targeted therapies and personalized medicine, for the benefit of patients. Current management options and present and future perspectives in this still evolving field are summarized.
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Púrpura Trombocitopénica Trombótica , Proteína ADAMTS13 , Empirismo , Humanos , Terapia Molecular Dirigida , Intercambio Plasmático , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/terapiaRESUMEN
Recently, we showed that ADAMTS13 circulates in an open conformation during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP). Although the cause of this conformational change remains elusive, ADAMTS13 is primarily closed in iTTP patients in remission with ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, as well as after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, immunoglobulin G from 18 acute iTTP patients was purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14 of 18 (78%) samples, proving that anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n = 197) that also included plasma samples from iTTP patients in remission in whom ADAMTS13 activity was <50%. The open ADAMTS13 conformation was found during acute iTTP, as well as in patients in remission with ADAMTS13 activity <50% and in half of the patients with ADAMTS13 activity >50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus, open ADAMTS13 is a hallmark of acute iTTP, as well as a novel biomarker that can be used to detect subclinical iTTP in patients in remission. Finally, a long-term follow-up study in 1 iTTP patient showed that the open conformation precedes a substantial drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management.
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Proteína ADAMTS13/sangre , Autoanticuerpos/sangre , Púrpura Trombocitopénica Idiopática/sangre , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Conformación Proteica , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Rituximab/administración & dosificaciónRESUMEN
BACKGROUND: Thrombotic microangiopathies (TMAs) occurring in the postpartum period may be difficult to manage. They present as the combination of mechanical hemolytic anemia and consumption thrombocytopenia due to endothelial dysfunction. The cause of this endothelial aggression can be multiple: thrombocytopenic thrombotic purpura (TTP), HELLP syndrome, antiphospholipid syndrome, atypical hemolytic and uremic syndrome or acute fatty liver of pregnancy. TTP results from a severe deficiency of ADAMTS13, which is a protease cleaving specifically von Willebrand factor chiefly produced by liver cells. There are two main causes, the production of anti-ADAMTS13 auto-antibodies and, more rarely, a genetic deficiency in ADAMTS13. First-line treatment is based on plasma exchange. HELLP syndrome occurs in the third trimester of pregnancy usually in association with preeclampsia and represents a form of TMA characterized by damage to the sinusoidal capillaries of the liver. Prompt delivery is the main treatment. We present a case illustrating the challenges in discriminating between different postpartum TMAs, with a focus on the distinction between TTP and HELLP syndrome. Specifically, we highlight how acute liver failure (ALF) stemming from HELLP may lead to TTP with a spectacular response to plasma exchanges. CASE: A 28-year-old, 33 + 4 weeks pregnant woman presented with severe preeclampsia complicated by ALF in the setting of partial liver necrosis, disseminated intravascular coagulation, microangiopathic hemolytic anemia and acute kidney injury. Greatly diminished levels of ADAMTS13 (< 5%) activity and neurological impairment suggested an initial diagnosis of thrombotic thrombocytopenic purpura (TTP). Therapeutic plasma exchange (TPE) was initiated and complete renal, neurological, hematological and hepatic recovery was observed. Secondary TTP induced by ALF due to HELLP syndrome was the final diagnosis. CONCLUSION: Our case addresses the overlapping nature of postpartum TMAs and raises the possibility that HELLP-induced ALF may constitute an additional mechanism resulting in TTP, thereby opening a possible indication for TPE.
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Síndrome HELLP/diagnóstico , Fallo Hepático Agudo/complicaciones , Púrpura Trombocitopénica Trombótica/diagnóstico , Proteína ADAMTS13/inmunología , Adulto , Anticuerpos/sangre , Diagnóstico Diferencial , Coagulación Intravascular Diseminada/etiología , Femenino , Síndrome HELLP/terapia , Humanos , Hígado/patología , Necrosis , Intercambio Plasmático , Preeclampsia/etiología , Embarazo , Púrpura Trombocitopénica Trombótica/etiologíaRESUMEN
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia linked to disseminated microvascular platelet rich-thrombi. TTP is specifically related to a severe deficiency in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), the specific von Willebrand factor-cleaving protease. ADAMTS13 deficiency is most frequently acquired via ADAMTS13 autoantibodies, but rarely, it is inherited via mutations of the ADAMTS13 gene. The first acute episode of TTP usually occurs during adulthood, with a predominant anti-ADAMTS13 autoimmune etiology. In rare cases, however, TTP begins as soon as childhood, with frequent inherited forms. TTP is â¼2-fold more frequent in women, and its outcome is characterized by a relapsing tendency. Rapid recognition of TTP is crucial to initiate appropriate treatment. The first-line therapy for acute TTP is based on daily therapeutic plasma exchange supplying deficient ADAMTS13, with or without steroids. Additional immune modulators targeting ADAMTS13 autoantibodies are mainly based on steroids and the humanized anti-CD20 monoclonal antibody rituximab. In refractory or unresponsive TTP, more intensive therapies including twice-daily plasma exchange; pulses of cyclophosphamide, vincristine, or cyclosporine A; or salvage splenectomy are considered. New drugs including N-acetylcysteine, bortezomib, recombinant ADAMTS13, and caplacizumab show promise in the management of TTP. Also, long-term follow-up of patients with TTP is crucial to identify the occurrence of other autoimmune diseases, to control relapses, and to evaluate psychophysical sequelae. Further development of both patients' registries worldwide and innovative drugs is still needed to improve TTP management.
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Proteína ADAMTS13/deficiencia , Púrpura Trombocitopénica Trombótica , Caracteres Sexuales , Acetilcisteína/uso terapéutico , Adulto , Edad de Inicio , Anticuerpos Monoclonales/uso terapéutico , Autoanticuerpos/sangre , Bortezomib/uso terapéutico , Femenino , Humanos , Factores Inmunológicos/uso terapéutico , Masculino , Mutación , Intercambio Plasmático , Púrpura Trombocitopénica Trombótica/sangre , Púrpura Trombocitopénica Trombótica/genética , Púrpura Trombocitopénica Trombótica/terapia , Anticuerpos de Dominio Único/uso terapéuticoRESUMEN
In autoantibody-mediated autoimmune diseases, autoantibody profiling allows patients to be stratified and links autoantibodies with disease severity and outcome. However, in immune-mediated thrombotic thrombocytopenic purpura (iTTP) patients, stratification according to antibody profiles and their clinical relevance has not been fully explored. We aimed to develop a new type of autoantibody profiling assay for iTTP based on the use of anti-idiotypic antibodies. Anti-idiotypic antibodies against 3 anti-spacer autoantibodies were generated in mice and were used to capture the respective anti-spacer idiotopes from 151 acute iTTP plasma samples. We next deciphered these anti-spacer idiotope profiles in iTTP patients and investigated whether these limited idiotope profiles could be linked with disease severity. We developed 3 anti-idiotypic antibodies that recognized particular idiotopes in the anti-spacer autoantibodies II-1, TTP73 or I-9, that are involved in ADAMTS13 binding; 35%, 24% and 42% of patients were positive for antibodies with the II-1, TTP73 and I-9 idiotopes, respectively. Stratifying patients according to the corresponding 8 anti-spacer idiotope profiles provided a new insight into the anti-spacer II-1, TTP73 and I-9 idiotope profiles in these patients. Finally, these limited idiotope profiles showed no association with disease severity. We successfully developed 3 anti-idiotypic antibodies that allowed us to determine the profiles of the anti-spacer II-1, TTP73 and I-9 idiotopes in iTTP patients. Increasing the number of patients and/or future development of additional anti-idiotypic antibodies against other anti-ADAMTS13 autoantibodies might allow idiotope profiles of clinical, prognostic value to be identified.
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Anticuerpos Antiidiotipos/inmunología , Autoanticuerpos/inmunología , Susceptibilidad a Enfermedades/inmunología , Púrpura Trombocitopénica Trombótica/inmunología , Proteína ADAMTS13/inmunología , Proteína ADAMTS13/metabolismo , Animales , Autoantígenos/metabolismo , Ensayo de Inmunoadsorción Enzimática , Epítopos/inmunología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Unión Proteica/inmunología , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
Child-onset thrombotic thrombocytopenic purpura (TTP) is a rare entity of thrombotic microangiopathy (TMA). The pathophysiology of the disease is based on a severe functional deficiency of ADAMTS13 (activity <10%), the specific von Willebrand factor (VWF)-cleavage protease. This deficiency may be either acquired (associated anti-ADAMTS13 autoantibodies) or congenital (resulting from biallelic mutations of ADAMTS13 gene). ADAMTS13 deficiency is responsible for the accumulation of high molecular weight multimers of VWF and the formation of platelet thrombi in the microcirculation. Consequently, microangiopathic hemolytic anemia and consumption thrombocytopenia are associated with organ ischemia. The differential diagnosis with other TMAs, autoimmune cytopenias or hematological malignancies may be challenging. The exploration of ADAMTS13 (activity, antibodies, antigen, ADAMTS13 gene) supports the diagnosis of TTP. The first-line treatment of the acute phase of TTP is based on plasmatherapy. In congenital TTP, patients with a chronic disease benefit from a prophylactic plasmatherapy. In autoimmune TTP, steroids and B-cells depleting therapies increasingly are used together with plasma exchange. Long-term follow-up including the monitoring of ADAMTS13 activity is mandatory. A severe decrease in ADAMTS13 activity (<10%) may predict relapses and preemptive B-cell depletion with rituximab can be used to prevent relapses.
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Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/etiología , Púrpura Trombocitopénica Trombótica/terapia , Factores de Edad , Biomarcadores , Niño , HumanosRESUMEN
Pregnancy is a well-established risk factor for venous thromboembolism and is associated with a state of hypercoagulability. The use of sensitive and specific biological markers to predict risk factors for thrombosis is essential during pregnancy. Our objective was to investigate the usefulness of thrombin generation test (TGT) as a marker to predict the risk of thrombosis in high risk venous thrombosis (HRVT) pregnancies compared to normal pregnancies. This retrospective study enrolled 134 women with HRVT pregnancies, 78 of whom had monozygotic, spontaneous and untreated pregnancies and formed the study group. The control group comprised 106 women with normal pregnancies. Routine assessment of coagulation activation markers: fibrinogen, D-dimer, prothrombin fragments 1 + 2 (F1 + 2), thrombin-antithrombin complexes (TAT) and fibrin monomer complexes (FMC) was performed every 5 weeks in the study group to detect a possible pathological state of hypercoagulability. TGT was performed using platelet-free plasma, 1 and 5 pM tissue factor (TF), supplemented by phospholipids (PL) ± thrombomodulin. Fibrinogen, D-dimer, F1 + 2, and TAT, but not FMC, increased significantly throughout pregnancy in both groups but no difference was shown between the groups. TGT showed an early increase in thrombin generation in both groups, which stabilized during the second month of pregnancy. No correlation was demonstrated between thrombin generation parameters and coagulation activation markers. Based on our results, TGT did not prove conclusive as a marker to predict the risk of thrombosis in HRVT pregnancies. Finding a sensitive and specific biological marker to predict thrombosis risk requires further investigation.
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Pruebas de Coagulación Sanguínea/normas , Complicaciones Hematológicas del Embarazo/diagnóstico , Embarazo de Alto Riesgo , Trombina/biosíntesis , Trombosis de la Vena/diagnóstico , Adolescente , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Embarazo , Estudios Retrospectivos , Sensibilidad y Especificidad , Adulto JovenAsunto(s)
Proteína ADAMTS13/inmunología , Autoanticuerpos/inmunología , Trasplante de Riñón/efectos adversos , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/etiología , Adulto , Biomarcadores , Humanos , Inmunoglobulina G/inmunología , Inmunohistoquímica , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Trombótica/sangreRESUMEN
ABSTRACT: Pregnancy-onset thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening disease of which diagnosis and management requires experienced multidisciplinary teams. The mechanisms responsible for a deficiency in the disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) leading to pregnancy-onset TTP may be congenital or acquired, and studying ADAMTS13 conformation could be of interest. The differential diagnosis between TTP and other pregnancy-associated thrombotic microangiopathies (TMA) is often challenging. Our retrospective multicenter study highlights the significance and the challenges associated with pregnancy-onset TTP and childbirth in terms of diagnosis, obstetric management, and follow-up aspects. Among 1174 pregnancy-onset TMA enrolled in the French Registry for TMA from 2000 to 2020, we identified 108 pregnancy-onset TTP: 52 immune-mediated TTP (iTTP, 48.1%), 27 acquired TTP of unidentified mechanism (uTTP, 25%), and 29 congenital TTP (cTTP, 26.9%). Data show that maternal outcome is good (survival rate: 95%) and fetal outcome is linked to the gestational age at the onset of the disease (survival rate: 75.5%). Three distinct entities with different natural histories emerged: pregnancy-onset iTTP appears similar to idiopathic iTTP, with an open ADAMTS13 conformation, and is marked by a relapse risk independent of subsequent pregnancies; pregnancy-onset uTTP appears to have a different pathophysiology with an unexpected open ADAMTS13 conformation and a very low relapse risk independent of subsequent pregnancies; finally, pregnancy-onset cTTP is characterized by the necessity of pregnancy as a systematic and specific trigger and a need for prophylactic plasmatherapy for subsequent pregnancies. This trial was registered at www.clinicaltrials.gov as #NCT00426686, and at the Health Authority and the French Ministry of Health (P051064/PHRC AOM05012).
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Púrpura Trombocitopénica Trombótica , Microangiopatías Trombóticas , Embarazo , Femenino , Humanos , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/epidemiología , Púrpura Trombocitopénica Trombótica/terapia , Estudios de Seguimiento , Estudios Retrospectivos , RecurrenciaRESUMEN
Background: A disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS-13) is the specific von Willebrand factor-cleaving protease and circulates in a closed and latent conformation due to a spacer/CUB1 domain interaction. ADAMTS-13 is allosterically activated after binding of its substrate or antibodies, inducing an open conformation. Recently, we suggested a potential role of plasmin (fibrinolysin) in hemostasis disorders reported in most patients with hemophagocytic lymphohistiocytosis (HLH), a rare and life-threatening condition related to a severe systemic inflammatory state. Most patients with HLH had a partial ADAMTS-13 deficiency, and plasmin could induce a truncation of the C-terminal part of ADAMTS-13 and thus an open conformation. Objectives: To understand the effect of plasmin on ADAMTS-13, our study aimed to investigate ADAMTS-13 conformation in patients with HLH. Methods: Forty-five critically ill patients with HLH were prospectively enrolled between April 2015 and December 2018. ADAMTS-13 activity was measured by fluorescent resonance energy transfer-VWF73 assay, ADAMTS-13 antigen, and conformation with our homemade 3H9-enzyme-linked immunosorbent assay and 1C4-enzyme-linked immunosorbent assay. Results: ADAMTS-13 activity ranged from <10 to 65 IU/dL, and 41 of the 45 patients had a quantitative deficiency in ADAMTS-13 (activity <50 IU/dL). Twenty patients had a severe ADAMTS-13 deficiency (activity <20 IU/dL). ADAMTS-13 conformation was folded in all patients under normal conditions. Surprisingly, the switch of ADAMTS-13 conformation expected with the monoclonal antibody 17G2 (anti-CUB1) was disturbed in 6 patients (activity <20 IU/dL). Conclusion: Our study reported that ADAMTS-13 conformation is closed in HLH and provides an indirect proof that plasmin is not able to massively degrade ADAMTS-13. Further studies on glycosylation and citrullination profiles of ADAMTS-13 are needed to understand their role in HLH.
RESUMEN
BACKGROUND: Laboratory diagnosis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains challenging when ADAMTS-13 activity ranges between 10% and 20%. To prevent misdiagnosis, open ADAMTS-13 conformation gained clinical attention as a novel biomarker, especially to diagnose acute iTTP in patients with diagnostic undecisive ADAMTS-13 activity. Plasma ADAMTS-13 conformation analysis corrects for ADAMTS-13 antigen, with both parameters being characterized in enzyme-linked immunosorbent assay (ELISA)-based reference assays requiring expert technicians. OBJECTIVES: To design ADAMTS-13 antigen and conformation assays on automated, easy-to-use fiber optic surface plasmon resonance (FO-SPR) technology to promote assay accessibility and diagnose challenging iTTP patients. METHODS: ADAMTS-13 antigen and conformation assays were designed on FO-SPR technology. Plasma of 20 healthy donors and 20 acute iTTP patients were quantified, and data from FO-SPR and ELISA reference assays were compared. RESULTS: Following assay design, both antigen and conformation FO-SPR assays were optimized and characterized, presenting strong analytical sensitivity (detection limit of 0.001 µg/mL) and repeatability (interassay variation of 14.4%). Comparative analysis suggested positive correlation (Spearman r of 0.92) and good agreement between FO-SPR and ELISA assays. As expected, FO-SPR assays showed a closed or open ADAMTS-13 conformation in healthy donors and acute iTTP patients, respectively. CONCLUSION: Both ADAMTS-13 antigen and conformation assays were transferred onto automated, easy-to-use FO-SPR technology, displaying potent analytical sensitivity and reproducibility. ADAMTS-13 antigen and conformation were determined for healthy donors and acute iTTP patients showing strong correlation with ELISA reference. Introducing FO-SPR technology in clinical context could support routine diagnosis of acute iTTP patients, notably when ADAMTS-13 activity fluctuates between 10% and 20%.
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Proteína ADAMTS13 , Ensayo de Inmunoadsorción Enzimática , Púrpura Trombocitopénica Trombótica , Resonancia por Plasmón de Superficie , Proteína ADAMTS13/sangre , Proteína ADAMTS13/inmunología , Humanos , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/sangre , Púrpura Trombocitopénica Trombótica/inmunología , Ensayo de Inmunoadsorción Enzimática/métodos , Estudios de Casos y Controles , Biomarcadores/sangre , Reproducibilidad de los Resultados , Conformación Proteica , Valor Predictivo de las Pruebas , Inmunoensayo/métodos , Automatización de Laboratorios , Femenino , MasculinoRESUMEN
BACKGROUND: ADAMTS-13 adopts an open conformation in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in acute phase while being closed in healthy donors. We reported that a substantial number of patients with iTTP in remission with restored ADAMTS-13 activity (>50%) still had an open ADAMTS-13 conformation, although a closed conformation is expected given the extent of remission. OBJECTIVES: To investigate whether open ADAMTS-13, represented by a conformation index >0.5, is associated with a risk of earlier ADAMTS-13 and/or clinical relapse. METHODS: We collected follow-up data (ADAMTS-13 parameters, ADAMTS-13 and clinical relapse, and treatment) from 81 patients with iTTP in remission with ADAMTS-13 activity >50%. RESULTS: During follow-up, 19 ADAMTS-13 and 10 clinical relapses were reported (median follow-up period, 20 months). First, open or closed ADAMTS-13 conformation was dichotomized based on the 0.5 conformation index cutoff. Open ADAMTS-13 (conformation index, >0.5) was not identified as a risk factor for ADAMTS-13 and clinical relapse (log-rank test and Cox regression model). In contrast, by identifying the optimal conformation index cutoff for relapse prediction, using classification and regression tree analysis, a conformation index >0.645 and >0.835 was shown to be a risk factor for ADAMTS-13 relapse (hazard ratio, 3.3; 95% CI, 1.3-8.3; P = .01) and clinical relapse (hazard ratio, 4.4; 95% CI, 1.3-15.3; P = .02), respectively. CONCLUSION: Patients with open ADAMTS-13 with a conformation index >0.645 and >0.835 have a >3- and >4-fold higher risk of earlier ADAMTS-13 and clinical relapse, respectively. Hence, ADAMTS-13 conformation index could be used to complement ADAMTS-13 activity monitoring to timely notice ADAMTS-13 relapse and prevent clinical relapse.
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Proteína ADAMTS13 , Púrpura Trombocitopénica Trombótica , Humanos , Autoanticuerpos , Modelos de Riesgos Proporcionales , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/terapia , Recurrencia , Factores de RiesgoRESUMEN
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy (TMA) related to a severe ADAMTS13 deficiency, the specific von Willebrand factor (VWF)-cleaving protease. This deficiency is often immune-mediated (iTTP) and related to the presence of anti-ADAMTS13 autoantibodies that enhance its clearance or inhibit its VWF processing activity. iTTP management may be challenging at extreme ages of life. International cohorts of people with TTP report delayed diagnoses and misdiagnoses in children and elderly people. Child-onset iTTP shares many features with adult-onset iTTP: a female predominance, an idiopathic presentation, and the presence of neurological disorders and therapeutic strategies. Long-term follow-ups and a transition from childhood to adulthood are crucial to preventing iTTP relapses, in order to identify the occurrence of other autoimmune disorders and psychosocial sequelae. In contrast, older iTTP patients have an atypical clinical presentation, with delirium, an atypical neurological presentation, and severe renal and cardiac damages. They also have a poorer response to treatment and prognosis. Long-term sequelae are highly prevalent in older patients. Prediction scores for iTTP diagnoses are not used for children and have a lower sensitivity and specificity in patients over 60 years old. ADAMTS13 remains the unique biological marker that is able to definitely confirm or rule out the diagnosis of iTTP and predict relapses during follow-ups.
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Hemostasis impairment represents the most threatening consequence of Viperidae envenoming, notably with Bothrops genus. In the French departments of America, B. atrox envenomation in French Guiana may lead to bleeding while B. lanceolatus envenomation in Martinique to thrombosis. Bleeding related to B. atrox envenomation is attributed to vascular damage mediated by venom metalloproteinases and blood uncoagulable state resulting from thrombocytopenia and consumptive coagulopathy. Thrombosis related to B. lanceolatus envenomation are poorly understood. We aimed to compare the effects of B. atrox and B. lanceolatus venoms in the rat to identify the determinants of the hemorrhagic versus thrombotic complications. Viscoelastometry (ROTEM), platelet count, plasma fibrinogen, thrombin generation assay, fibrinography, endothelial (von Willebrand factor, ADAMTS13 activity, ICAM-1, and soluble E-selectin), and inflammatory biomarkers (IL-1ß, IL-6, TNF-α, MCP-1, and PAI-1) were determined in blood samples obtained at H3, H6, and H24 after the subcutaneous venom versus saline injection. In comparison to the control, initial fibrinogen consumption was observed with the two venoms while thrombocytopenia and reduction in the clot amplitude only with B. atrox venom. Moreover, we showed an increase in thrombin generation at H3 with the two venoms, an increase in fibrin generation accompanied with hyperfibrinogenemia at H24 and an increase in inflammatory biomarkers with B. lanceolatus venom. No endothelial damage was found with the two venoms. To conclude, our data support two-sided hemostasis complications in Bothrops envenoming with an initial risk of hemorrhage related to platelet consumption and hypocoagulability followed by an increased risk of thrombosis promoted by the activated inflammatory response and rapid-onset fibrinogen restoration.
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Trastornos de la Coagulación Sanguínea , Bothrops , Venenos de Crotálidos , Mordeduras de Serpientes , Trombocitopenia , Trombosis , Ratas , Animales , Trombina/efectos adversos , Venenos de Crotálidos/toxicidad , Hemostasis , Hemorragia , Fibrinógeno , Trombosis/inducido químicamente , Biomarcadores , Bothrops/fisiología , Mordeduras de Serpientes/complicacionesRESUMEN
Thrombotic thrombocytopenic purpura (iTTP) and atypical hemolytic-uremic syndrome (aHUS), once in remission, may cause long-term symptoms, among which mental-health impairments may be difficult to detect. We conducted telephone interviews 72 [48-84] months after ICU discharge to assess symptoms of anxiety, depression, and posttraumatic stress disorder (PTSD) and the 36-item Short Form questionnaire (SF-36). Of 103 included patients, 52 had iTTP and 51 aHUS; 74% were female, median age was 39 y (31-54), and 39 (38%) patients were still taking treatment. Symptoms of anxiety, PTSD and depression were present in 50%, 27% and 14% of patients, respectively, with no significant difference between the iTTP and aHUS groups. Patients with PTSD symptoms had significantly greater weight gain and significantly worse perceived physical and/or emotional wellbeing, anxiety symptoms, and depression symptoms. The SF-36 physical and mental components indicated significantly greater quality-of-life impairments in patients with vs. without PTSD symptoms and in those with aHUS and PTSD vs. iTTP with or without PTSD. In the aHUS group, quality of life was significantly better in patients with vs. without eculizumab treatment. Factors independently associated with PTSD symptoms were male sex (odds ratio [OR], 0.11; 95%CI, 0.02-0.53), platelet count ≤20 G/L at acute-episode presentation (OR, 2.68; 1.01-7.38), and current treatment (OR, 2.69; 95%CI, 1.01-7.36). Mental-health screening should be routine in patients with iTTP and aHUS to ensure appropriate care.
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Síndrome Hemolítico Urémico Atípico , Púrpura Trombocitopénica Trombótica , Trastornos por Estrés Postraumático , Humanos , Masculino , Femenino , Adulto , Púrpura Trombocitopénica Trombótica/complicaciones , Púrpura Trombocitopénica Trombótica/diagnóstico , Trastornos por Estrés Postraumático/epidemiología , Calidad de Vida , Síndrome Hemolítico Urémico Atípico/diagnóstico , Síndrome Hemolítico Urémico Atípico/etiología , Síndrome Hemolítico Urémico Atípico/terapia , SobrevivientesRESUMEN
BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic disorder, with 1.5 to 6.0 cases per million per year. The majority of patients with TTP develop inhibitory autoantibodies that predominantly target the spacer domain of ADAMTS-13. ADAMTS-13 is responsible for cleaving von Willebrand factor (VWF) multimers, thereby regulating platelet adhesion at sites of high-vascular shear stress. Inhibition and/or clearance of ADAMTS-13 by pathogenic autoantibodies results in accumulation of VWF multimers that promotes the formation of platelet-rich microthrombi. Previously, we have shown that insertion of a single N-glycan (NGLY) in the spacer domain prevents the binding of antispacer domain antibodies. OBJECTIVES: To explore whether NGLY mediated shielding of the ADAMTS-13 spacer domain effectively prevents binding of pathogenic antispacer autoantibodies in patients with immune-mediated TTP (iTTP). METHODS: We screened 5 NGLY-ADAMTS-13 variants (NGLY3, NGLY7, NGLY8, NGLY3+7, and NGLY3+8) for binding of autoantibodies and for their activity in the presence and absence of 50 samples derived from patients with iTTP. RESULTS: NGLY variants showed greatly reduced antibody binding, down to 27% of wild-type (wt) ADAMTS-13 binding. Moreover, NGLY variants of ADAMTS-13 remained more active in FRETS-VWF73 assay in the presence of the plasma samples from these 50 patients with acute phase iTTP when compared with wtADAMTS-13. On average, wtADAMTS-13 activity was reduced to 37% of regular levels in the presence of plasma, while NGLY3 and NGLY3+7 remained 69% and 81% active, respectively. CONCLUSION: These results reinforce our previous findings that NGLYs shield ADAMTS-13 from antibody binding and hence restore ADAMTS-13 activity in the presence of autoantibodies.
Asunto(s)
Púrpura Trombocitopénica Idiopática , Púrpura Trombocitopénica Trombótica , Trombosis , Humanos , Proteína ADAMTS13 , Factor de von Willebrand/metabolismo , Plaquetas/metabolismo , AutoanticuerposRESUMEN
Heart metastases from urothelial carcinoma of the bladder have rarely been reported in the literature. We present a case complicated by symptomatic disseminated intravascular coagulation in a 67-year-old woman. A rapid and sustained recovery from hemostatic troubles was obtained following fibrinogen supplementation combined with second-line paclitaxel chemotherapy.