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ABSTRACT: Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare autosomal recessive, life-threatening disorder caused by a severe deficiency of the plasma enzyme, ADAMTS13. The current estimated prevalence of hTTP in different regions of the world, 0.5 to 2.0 patients per million, is determined by the frequency of diagnosed patients. To evaluate more accurately the worldwide prevalence of hTTP, and also the prevalence within distinct ethnic groups, we used data available in exome and genome sequencing of 807 162 (730 947 exomes, 76 215 genomes) subjects reported recently by the Genome Aggregation Database (gnomAD-v4.1). Among 1 614 324 analyzed alleles in the gnomAD population we identified 6321 distinct ADAMTS13 variants. Of these, 758 were defined as pathogenic; 140 (18%) variants had been previously reported and 618 (82%) were novel (predicted as pathogenic). In total 10 154 alleles (0.6%) were carrying the reported or predicted pathogenic variants; 7759 (77%) with previously reported variants. Considering all 758 pathogenic variants and also only the 140 previously reported variants, we estimated a global hTTP prevalence of 40 and 23 cases per 106, respectively. Considering only the 140 previously reported variants, the highest estimated prevalence was in East Asians (42 per 106). The estimated prevalences of other populations were: Finnish, 32 per 106; non-Finnish Europeans, 28 per 106; Admixed Americans, 19 per 106; Africans/African Americans, 6 per 106; and South Asians, 4 per 106. The lowest prevalences were Middle Eastern, 1 per 106 and Ashkenazi Jews, 0.7 per 106. This population-based genetic epidemiology study reports that hTTP prevalence is substantially higher than the currently estimated prevalence based on diagnosed patients. Many patients with hTTP may not be diagnosed or may have died during the neonatal period.
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Púrpura Trombocitopénica Trombótica , Humanos , Púrpura Trombocitopénica Trombótica/genética , Púrpura Trombocitopénica Trombótica/epidemiología , Prevalencia , Pruebas Genéticas , Proteína ADAMTS13/genética , Alelos , Salud Global , Femenino , Mutación , Predisposición Genética a la EnfermedadRESUMEN
Intensive care physicians may assume the primary care of patients with transplant-associated thrombotic microangiopathy (TA-TMA), an uncommon but potentially critical complication of hematopoietic stem cell transplants (HSCTs) and solid organ transplants. TA-TMA can have a dramatic presentation with multiple organ dysfunction syndrome (MODS) associated with high morbidity and mortality. The typical presenting clinical features are hemolytic anemia, thrombocytopenia, refractory hypertension, proteinuria and worsening renal failure. Intestinal involvement, with abdominal pain, nausea and vomiting, gastrointestinal bleeding, and ascites are also common. Cardiopulmonary involvement may develop from various causes including pulmonary arteriolar hypertension, pleural and pericardial effusions, and diffuse alveolar hemorrhage. Due to other often concurrent complications after HSCT, early diagnosis and effective management of TA-TMA may be challenging. Close collaboration between ICU and transplant physicians, along with other relevant specialists, is needed to best manage these patients. There are currently no approved therapies for the treatment of TA-TMA. Plasma exchange and rituximab are not recommended unless circulating factor H (CFH) antibodies or thrombotic thrombocytopenic purpura (TTP; ADAMTS activity < 10%) are diagnosed or highly suspected. The role of the complement pathway activation in the pathophysiology of TA-TMA has led to the successful use of targeted complement inhibitors, such as eculizumab. However, the relatively larger studies using eculizumab have been mostly conducted in the pediatric population with limited data on the adult population. This review is focused on the role of intensive care physicians to emphasize the clinical approach to patients with suspected TA-TMA and to discuss diagnosis and treatment strategies.
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Trasplante de Células Madre Hematopoyéticas , Hipertensión , Trasplante de Órganos , Microangiopatías Trombóticas , Adulto , Humanos , Niño , Microangiopatías Trombóticas/etiología , Microangiopatías Trombóticas/terapia , Microangiopatías Trombóticas/diagnóstico , Hipertensión/complicaciones , Insuficiencia Multiorgánica/terapia , Insuficiencia Multiorgánica/complicaciones , Trasplante de Órganos/efectos adversos , Células Madre Hematopoyéticas , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
ABSTRACT: Although it is caused by a single-nucleotide mutation in the ß-globin gene, sickle cell anemia (SCA) is a systemic disease with complex, incompletely elucidated pathologies. The mononuclear phagocyte system plays critical roles in SCA pathophysiology. However, how heterogeneous populations of hepatic macrophages contribute to SCA remains unclear. Using a combination of single-cell RNA sequencing and spatial transcriptomics via multiplexed error-robust fluorescence in situ hybridization, we identified distinct macrophage populations with diversified origins and biological functions in SCA mouse liver. We previously found that administering the von Willebrand factor (VWF)-cleaving protease ADAMTS13 alleviated vaso-occlusive episode in mice with SCA. Here, we discovered that the ADAMTS13-cleaved VWF was cleared from the circulation by a Clec4f+Marcohigh macrophage subset in a desialylation-dependent manner in the liver. In addition, sickle erythrocytes were phagocytized predominantly by Clec4f+Marcohigh macrophages. Depletion of macrophages not only abolished the protective effect of ADAMTS13 but exacerbated vaso-occlusive episode in mice with SCA. Furthermore, promoting macrophage-mediated VWF clearance reduced vaso-occlusion in SCA mice. Our study demonstrates that hepatic macrophages are important in the pathogenesis of SCA, and efficient clearance of VWF by hepatic macrophages is critical for the protective effect of ADAMTS13 in SCA mice.
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Anemia de Células Falciformes , Enfermedades Vasculares , Ratones , Animales , Factor de von Willebrand/genética , Hibridación Fluorescente in Situ , Anemia de Células Falciformes/patología , Macrófagos/patología , Proteína ADAMTS13/genéticaRESUMEN
BACKGROUND: Current ADAMTS13 activity assays are important for diagnosing thrombotic thrombocytopenic purpura (TTP) but are unreliable to assay ADAMTS13 activity in animal models. The Cattle-FRETS71 assay is capable of detecting ADAMTS13 activity in plasma from multiple animal species, making it a potentially useful reagent at all stages of clinical research. The performance of Cattle-FRETS71 in TTP diagnosis is not yet known. OBJECTIVES: We evaluated the performance of the Cattle-FRETS71 substrate against the human FRETS-rVWF71 and the FRETS-VWF73 commercial substrates in human plasma and serum samples to validate its utility in diagnosing TTP in patients. METHODS: Internal validation was performed using heparinized plasma samples (n = 81). External validation was a blinded study using serum samples from the Oklahoma TTP Registry (n = 118, collected 2004-2014) that had been initially assayed by FRETS-VWF73 within 1 year of collection. Additional validation was performed with citrated plasma samples with variable ADAMTS13 activities (n = 32) that were analyzed by FRETS-VWF73. RESULTS: There was an excellent correlation (r = 0.94) between Cattle-FRETS71 and FRETS-rVWF71 for assayed heparinized plasma samples (n = 81). Assay results between Cattle-FRETS71 and FRETS-VWF73 of Oklahoma TTP Registry serum samples (n = 118) and citrated plasma samples (n = 32) were comparably good (r = 0.81 and r = 0.85, respectively). CONCLUSION: The Cattle-FRETS71 assay is comparable with other assays in quantifying ADAMTS13 activity in human plasma collected from patients with documented or suspected TTP. The versatility of Cattle-FRETS71, combined with its specificity and sensitivity, makes it a useful tool for the standardization of ADAMTS13 activity across basic and clinical research paradigms.
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Púrpura Trombocitopénica Trombótica , Humanos , Bovinos , Animales , Púrpura Trombocitopénica Trombótica/diagnóstico , Colorantes Fluorescentes/química , Proteínas ADAM/metabolismo , Proteína ADAMTS13 , Transferencia Resonante de Energía de Fluorescencia/métodos , Factor de von Willebrand/química , Ácido CítricoRESUMEN
GATA3 immunohistochemistry stain of the bone marrow biopsy required to diagnose recurrent metastatic breast cancer.
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Neoplasias de la Mama , Púrpura Trombocitopénica Trombótica , Humanos , Femenino , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/patología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/patología , Médula Ósea/patología , Biopsia , Enfermedad CrónicaRESUMEN
Introduction: Severe COVID-19 is associated with an important increase of von Willebrand factor and mild lowering of ADAMTS13 activity that may, in the presence of a strong inflammatory reaction, increase the risk of acute thrombotic thrombocytopenic purpura (TTP). Although acute episodes of immune-mediated TTP associated with COVID-19 or SARS-CoV-2 vaccination have been reported, data about clinical evolution of hereditary TTP (hTTP) during the pandemic are scarce. Method: We conducted a survey among adult patients of the International Hereditary TTP Registry about SARS-CoV-2 vaccination, COVID-19, and occurrence of acute hTTP episodes. Results: Of 122 adult hTTP patients invited to participate, 86 (70.5%) responded. Sixty-five had been vaccinated (75.6%), of which 14 had received in addition a booster, resulting in 139 individual vaccine shots. Although vaccinations in patients on plasma prophylaxis were done within 1 week of the last plasma infusion, all 23 patients treated with plasma on demand were vaccinated without prior plasma infusions. One patient on uninterrupted weekly plasma infusions presented within 3 days from his second vaccination with neurological symptoms and computed tomography scan 9 days later showed subacute ischemic/hemorrhagic frontal lobe infarction. A second male patient developed acute myocarditis after his second dose of mRNA-1273 vaccine. Twelve (14%) patients had COVID-19, associated with an acute hTTP episode in three of them: one patient had a transient ischemic attack, one a stroke, and a pregnant woman was hospitalized to intensify plasma treatment. Discussion: The risk of an acute episode triggered by COVID-19 seems higher than following vaccination in hTTP patients, who can be safely vaccinated against SARS-CoV-2.
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Vaso-occlusive episode (VOE) is a common and critical complication of sickle cell disease (SCD). Its pathogenesis is incompletely understood. von Willebrand factor (VWF), a multimeric plasma hemostatic protein synthesized and secreted by endothelial cells and platelets, is increased during a VOE. However, whether and how VWF contributes to the pathogenesis of VOE is not fully understood. In this study, we found increased VWF levels during tumor necrosis factor (TNF)-induced VOE in a humanized mouse model of SCD. Deletion of endothelial VWF decreased hemolysis, vascular occlusion, and organ damage caused by TNF-induced VOE in SCD mice. Moreover, administering ADAMTS13, the VWF-cleaving plasma protease, reduced plasma VWF levels, decreased inflammation and vaso-occlusion, and alleviated organ damage during VOE. These data suggest that promoting VWF cleavage via ADAMTS13 may be an effective treatment for reducing hemolysis, inflammation, and vaso-occlusion during VOE.
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Anemia de Células Falciformes , Enfermedades Vasculares , Factor de von Willebrand , Proteína ADAMTS13/metabolismo , Proteína ADAMTS13/farmacología , Proteína ADAMTS13/uso terapéutico , Animales , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Eliminación de Gen , Hemólisis/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Ratones , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/etiología , Factor de von Willebrand/genética , Factor de von Willebrand/metabolismoRESUMEN
This review tells the story of my personal experience with thrombotic thrombocytopenic purpura (TTP). It begins with my first encounter with TTP 50 years ago when 2 sisters presented 2 years apart, both pregnant and both died. At that time, I knew nothing about hereditary TTP (hTTP), the risks of pregnancy, or effective treatments. In 1991, a year after I moved to Oklahoma, therapeutic plasma exchange (TPE) was established as an effective treatment. With the availability of effective treatment, the number of patients presenting with suspected TTP soared. The diagnosis of TTP was imprecise. I worked with the Oklahoma Blood Institute (OBI) to understand the management of TTP. Because the OBI provided all TPE procedures for most of Oklahoma, we saw all consecutive patients within a defined geographic area who were identified at a uniform time early in the course of their TTP, without selection or referral bias. It was an inception cohort; this became the Oklahoma TTP Registry. In 2001, we began a very successful collaboration with the University of Bern, Switzerland, to measure ADAMTS13 activity in all of our patients. From our patients, we learned that acquired, autoimmune TTP (iTTP) is a chronic disease with risks for cognitive impairment and depression. Recognition in 2012 of three sisters with hTTP was reminiscent of the beginning of my story. hTTP has risks for multiple severe morbidities, beginning at birth and especially during pregnancy. Future management of both iTTP and hTTP will be more effective and more convenient.
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Síndrome Hemolítico-Urémico , Púrpura Trombocitopénica Trombótica , Embarazo , Femenino , Recién Nacido , Humanos , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/terapia , Síndrome Hemolítico-Urémico/diagnóstico , Síndrome Hemolítico-Urémico/terapia , Proteínas ADAM , Proteína ADAMTS13 , Intercambio Plasmático/métodosAsunto(s)
Púrpura Trombocitopénica Trombótica , Accidente Cerebrovascular , Proteína ADAMTS13 , Humanos , Prevalencia , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/epidemiología , Púrpura Trombocitopénica Trombótica/genética , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genéticaRESUMEN
Microvascular thrombosis in patients with thrombotic thrombocytopenic purpura (TTP) is initiated by GPIbα-mediated platelet binding to von Willebrand factor (VWF). Binding of VWF to GPIbα causes activation of the platelet surface integrin αIIbß3. However, the mechanism of GPIbα-initiated activation of αIIbß3 and its clinical importance for microvascular thrombosis remain elusive. Deletion of platelet C-type lectin-like receptor 2 (CLEC-2) did not prevent VWF binding to platelets but specifically inhibited platelet aggregation induced by VWF binding in mice. Deletion of platelet CLEC-2 also inhibited αIIbß3 activation induced by the binding of VWF to GPIbα. Using a mouse model of TTP, which was created by infusion of anti-mouse ADAMTS13 monoclonal antibodies followed by infusion of VWF, we found that deletion of platelet CLEC-2 decreased pulmonary arterial thrombosis and the severity of thrombocytopenia. Importantly, prophylactic oral administration of aspirin, an inhibitor of platelet activation, and therapeutic treatment of the TTP mice with eptifibatide, an integrin αIIbß3 antagonist, reduced pulmonary arterial thrombosis in the TTP mouse model. Our observations demonstrate that GPIbα-mediated activation of integrin αIIbß3 plays an important role in the formation of thrombosis in TTP. These observations suggest that prevention of platelet activation with aspirin may reduce the risk for thrombosis in patients with TTP.
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Hipertensión Pulmonar , Púrpura Trombocitopénica Trombótica , Trombosis , Aspirina , Plaquetas/metabolismo , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Activación Plaquetaria , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Púrpura Trombocitopénica Trombótica/metabolismo , Trombosis/etiología , Factor de von Willebrand/metabolismoRESUMEN
Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare disorder caused by severe ADAMTS13 deficiency. Major morbidities and death at a young age are common. Although replacement of ADAMTS13 can prevent morbidities and death, current regimens of plasma prophylaxis are insufficient. We identified 226 patients with hTTP in 96 reports published from 2001 through 2020. Age at diagnosis was reported for 202 patients; 117 were female and 85 were male. The difference was caused by diagnosis of 34 women during pregnancy, suggesting that many men and nulliparous women are not diagnosed. Eighty-three patients had severe jaundice at birth; hTTP was suspected and effectively treated in only 3 infants. Of the 217 patients who survived infancy, 73 (34%) had major morbidities defined as stroke, kidney injury, or cardiac injury that occurred at a median age of 21 years. Sixty-two patients had stroke; 13 strokes occurred in children age 10 years or younger. Of the 54 patients who survived their initial major morbidity and were subsequently observed, 37 (69%) had sustained or subsequent major morbidities. Of the 39 patients who were observed after age 40 years, 20 (51%) had experienced a major morbidity. Compared with an age- and sex-matched US population, probability of survival was lower at all ages beginning at birth. Prophylaxis was initiated in 45 patients with a major morbidity; in 11 (28%), a major morbidity recurred after prophylaxis had begun. Increased recognition of hTTP and more effective prophylaxis started at a younger age are required to improve health outcomes.
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Púrpura Trombocitopénica Trombótica , Accidente Cerebrovascular , Adulto , Niño , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Morbilidad , Plasma , Embarazo , Púrpura Trombocitopénica Trombótica/diagnóstico , Recurrencia , Adulto JovenRESUMEN
A hematologist receives a call from a maternal-fetal medicine (MFM) physician about a previously healthy patient who became ill at 25 weeks' gestation. Her mental status is deteriorating. There are signs of fetal distress. Platelet count and hemoglobin are falling. The MFM physician is considering the hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome. For the hematologist, everything seems unfamiliar. Our goal is to provide hematologists with the fundamental knowledge required for understanding and managing these patients who become suddenly and seriously ill during pregnancy and in whom thrombocytopenia and microangiopathic hemolytic anemia are part of their presentation.
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Anemia Hemolítica/terapia , Complicaciones Hematológicas del Embarazo/terapia , Trombocitopenia/terapia , Anemia Hemolítica/diagnóstico , Manejo de la Enfermedad , Femenino , Humanos , Guías de Práctica Clínica como Asunto , Embarazo , Complicaciones Hematológicas del Embarazo/diagnóstico , Trombocitopenia/diagnósticoRESUMEN
Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare thrombotic microangiopathy characterized by severe congenital ADAMTS13 deficiency and recurring acute episodes causing morbidity and premature death. Information on the annual incidence and severity of acute episodes in patients with hTTP is largely lacking. This study reports prospective data on 87 patients from the Hereditary TTP Registry (clinicaltrials.gov #NCT01257269) for survival, frequency, and severity of acute episodes from enrollment until December 2019. The 87 patients, followed up for a median of 4.2 years (range, 0.01-15 years), had a median age at overt disease onset and at clinical diagnosis of 4.6 years and 18 years (range, 0.0-70 years for both), respectively. Forty-three patients received regular plasma prophylaxis, whereas 22 did not, and treatment changed over time or was unknown in the remaining 22. Forty-three patients experienced 131 acute episodes, of which 91 (69%) occurred in patients receiving regular prophylaxis. This resulted in an annual incidence of acute episodes of 0.36 (95% confidence interval [CI], 0.29-0.44) with regular plasma treatment and of 0.41 (95% CI, 0.30-0.56) without regular plasma treatment. More than one-third of acute episodes (n = 51) were documented in children <10 years of age at enrollment and were often triggered by infections. Their annual incidence of acute episodes was significantly higher than in patients aged >40 years (1.18 [95% CI, 0.88-1.55] vs 0.14 [95% CI, 0.08-0.23]). The prophylactic plasma infusion regimens used were insufficient to prevent acute episodes in many patients. Such regimens are burdensome, and caregivers, patients, and their guardians are reluctant to start regular plasma infusions, from which children particularly would benefit.