Relato de caso: Carcinoma indiferenciado de sítio primário oculto com metástases para pericárdio e Púrpura trombocitopênica trombótica paraneoplásica / Case report: Undifferentiated carcinoma of occult primary site with metastases to the pericardium and paraneoplastic thrombotic thrombocytopenic purpura

A associação entre neoplasia de sítio primário oculto e manifestações paraneoplásicas é um desafio diagnóstico e terapêutico. Este relato de caso descreve uma paciente com púrpura trombocitopênica trombótica (PTT) paraneoplásica como manifestação de um câncer primário oculto atendida pelo setor de Oncologia Clínica do Hospital do Servidor Público Municipal. A paciente apresentou queda importante da funcionalidade em pouco tempo devido a descompensação da neoplasia de base, evoluindo à óbito em poucos meses sem conseguir realizar qualquer tipo de tratamento. Este relato enfatiza a importância da avaliação clínica precisa e abrangente, além da abordagem multidisciplinar nos pacientes oncológicos que tanto sofrem com o estigma dessa doença. Palavras-chave: Neoplasia de Sítio Primário Oculto. Púrpura Trombocitopênica Trombótica Paraneoplásica. Metástases Cardíacas. Oncologia.

Post-cardiac surgery thrombotic thrombocytopenic purpura: presence of anti-ADAMTS13 autoantibodies at preoperative baseline.

Thrombotic thrombocytopenic purpura (TTP) rarely complicates acute inflammatory conditions such as surgery, including post-cardiac surgery. Review of 32 previously-reported cases of post-cardiac surgery TTP indicates that this disorder often occurs as early as 2-3 days following surgery, which seems too soon to implicate new formation of anti-ADAMTS13 autoantibodies as a consequence of surgery itself. We diagnosed post-cardiac surgery TTP in a 60-year-old female that began approximately 3 days post-coronary artery bypass surgery in which anti-ADAMTS13 autoantibodies were implicated. We therefore investigated whether anti-ADAMTS13 autoantibodies were also present in a preoperative blood sample. Inhibitory (neutralizing) anti-ADAMTS13 autoantibodies were detectable in the preoperative blood sample, suggesting that the role of surgery in precipitating TTP might be due to effects such as abrupt increase in postoperative von Willebrand factor levels and associated proinflammatory factors, rather than effects of surgery itself leading to the formation of de novo anti-ADAMTS13 autoantibodies.

Clinical Characteristics and Pharmacological Management of COVID-19 Vaccine-Induced Immune Thrombotic Thrombocytopenia With Cerebral Venous Sinus Thrombosis: A Review.

Importance: The COVID-19 pandemic saw one of the fastest developments of vaccines in an effort to combat an out-of-control pandemic. The 2 most common COVID-19 vaccine platforms currently in use, messenger RNA (mRNA) and adenovirus vector, were developed on the basis of previous research in use of this technology. Postauthorization surveillance of COVID-19 vaccines has identified safety signals, including unusual cases of thrombocytopenia with thrombosis reported in recipients of adenoviral vector vaccines. One of the devastating manifestations of this syndrome, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), is cerebral venous sinus thrombosis (CVST). This review summarizes the current evidence and indications regarding biology, clinical characteristics, and pharmacological management of VITT with CVST. Observations: VITT appears to be similar to heparin-induced thrombocytopenia (HIT), with both disorders associated with thrombocytopenia, thrombosis, and presence of autoantibodies to platelet factor 4 (PF4). Unlike VITT, HIT is triggered by recent exposure to heparin. Owing to similarities between these 2 conditions and lack of high-quality evidence, interim recommendations suggest avoiding heparin and heparin analogues in patients with VITT. Based on initial reports, female sex and age younger than 60 years were identified as possible risk factors for VITT. Treatment consists of therapeutic anticoagulation with nonheparin anticoagulants and prevention of formation of autoantibody-PF4 complexes, the latter being achieved by administration of high-dose intravenous immunoglobin (IVIG). Steroids, which can theoretically inhibit the production of new antibodies, have been used in combination with IVIG. In severe cases, plasma exchange should be used for clearing autoantibodies. Monoclonal antibodies, such as rituximab and eculizumab, can be considered when other therapies fail. Routine platelet transfusions, aspirin, and warfarin should be avoided because of the possibility of worsening thrombosis and magnifying bleeding risk. Conclusions and Relevance: Adverse events like VITT, while uncommon, have been described despite vaccination remaining the most essential component in the fight against the COVID-19 pandemic. While it seems logical to consider the use of types of vaccines (eg, mRNA-based administration) in individuals at high risk, treatment should consist of therapeutic anticoagulation mostly with nonheparin products and IVIG.

Survival after acute episodes of immune-mediated thrombotic thrombocytopenic purpura (iTTP) - cognitive functioning and health-related quality of life impact: a descriptive cross-sectional survey of adults living with iTTP in the United Kingdom.

OBJECTIVES: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare life-threatening thrombotic microangiopathy affecting adults with unpredictable disease onset and acute presentation. This study aimed to describe the health-related quality of life (HRQoL), cognitive functioning and work productivity of survivors following acute episode(s) of iTTP in the United Kingdom (UK). METHODS: An online survey was developed in collaboration with the TTP Network. Descriptive statistics were calculated for the health questionnaire Short Form Survey-36 Version 2 (SF-36v2), the Hospital Anxiety and Depression Score (HADS), the PROMIS Cognitive Function Abilities Subset - Short Form 6a (PROMIS CFAS - SF6a), and the Work Productivity and Activity Index: Specific Health Problem (WPAI-SHP), along with several iTTP-specific bespoke questions. RESULTS: Fifty participants were recruited between July-November 2019. The mean (standard deviation [SD]) standardized SF-36v2 physical and mental component scores were 42.16 (9.59) and 33.61 (12.34), lower than population norms. The mean (SD) standardized PROMIS CFAS - SF6a score was 39.69 (7.86), lower than population norms. HADS mean (SD) scores of 12.18 (3.14) and 11.78 (2.36) indicated moderate levels of anxiety and depression, respectively. Of those employed (58%), approximately 42.73% of participants reported work productivity loss due to their iTTP. Participants also reported experiencing flashbacks, fatigue interference in family, social and intimate life, and fears of relapse. DISCUSSION AND CONCLUSION: Regardless of recency of the last acute episode, participant scores signified impairments in all domains. Remission from an acute episode of disease does not signify the conclusion of care, but rather the requirement for long-term healthcare particularly focused on psychological support.

Thrombotic microangiopathy during pregnancy.

Pregnancy is a high-risk time for the development of different kinds of thrombotic microangiopathy (TMA). Three major syndromes including TTP (thrombotic thrombocytopenic purpura), PE/HELLP (preeclampsia/hemolysis, elevated liver function tests, low platelets), and aHUS (atypical hemolytic- uremic syndrome) should be sought in pregnancy-TMA. These severe disorders share multiple clinical features and overlaps and even the coexistence of more than one pathologic mechanism. Each of these disorders finally ends in endothelial damage and fibrin thrombi formation within the microcirculation that fragments RBCs (schystocytes), aggregates platelets, and creates ischemic injury in the targeted organs i.e.; kidney and brain. Although the mechanisms of these severe disorders have been revealed, pregnancy-related TMA still interfaces with diagnostic and therapeutic challenges. Here, we highlight the current knowledge of diagnosis and management of these complications during pregnancy.

Vaccine-Induced Immune Thrombotic Thrombocytopenia with Disseminated Intravascular Coagulation and Death following the ChAdOx1 nCoV-19 Vaccine.

Coronavirus is a novel human pathogen causing fulminant respiratory syndrome (COVID-19). Although COVID-19 is primarily a disease of the lungs with florid respiratory manifestations, there are increasing reports of cardiovascular, musculoskeletal, gastrointestinal, and thromboembolic complications. Developing an effective and reliable vaccine was emergently pursued to control the catastrophic spread of the global pandemic. We report a fatal case of vaccine-induced immune thrombotic thrombocytopenia (VITT) after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. We attribute this fatal thrombotic condition to the vaccine due to the remarkable temporal relationship. The proposed mechanism of VITT is production of rogue antibodies against platelet factor-4 resulting in massive platelet aggregation. Healthcare providers should be aware of the possibility of such fatal complication, and the vaccine recipients should be warned about the symptoms of VITT.

A case of thrombotic thrombocytopenic purpura associated with COVID-19.

Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease that can be triggered by different events, including viral infections. It presents as thrombotic microangiopathy and can lead to severe complications that often require management in the intensive care unit (ICU). We report a patient who presented with acquired TTP following COVID-19 infection. A 44-year-old woman presented to the emergency department with severe anemia, acute kidney injury and respiratory failure due to COVID-19. Clinical and laboratory findings were suggestive for thrombotic microangiopathy. On day 8 laboratory tests confirmed the diagnosis of acquired TTP. The patient needed 14 plasma exchanges, treatment with steroids, rituximab and caplacizumab and 18 days of mechanical ventilation. She completely recovered and was discharged home on day 51. Acquired TTP can be triggered by different events leading to immune stimulation. COVID-19 has been associated with different inflammatory and auto-immune diseases. Considering the temporal sequence and the lack of other possible causes, we suggest that COVID-19 infection could have been the triggering factor in the development of TTP. Since other similar cases have already been described, possible association between COVID and TTP deserves further investigation.

A critical evaluation of caplacizumab for the treatment of acquired thrombotic thrombocytopenic purpura.

Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) is a thrombotic microangiopathy caused by inhibitory autoantibodies against ADAMTS13 protein. Until recently, the combination of plasma exchange (PEX) and immunosuppression has been the standard front-line treatment in this disorder. However, aTTP-related mortality, refractoriness, and relapse are still a matter of concern. Areas covered: The better understanding of the pathophysiological mechanisms of aTTP has allowed substantial improvements in the diagnosis and treatment of this disease. Recently, the novel anti-VWF nanobody caplacizumab has been approved for acute episodes of aTTP. Caplacizumab is capable to block the adhesion of platelets to VWF, therefore inhibiting microthrombi formation in the ADAMTS13-deficient circulation. In this review, the characteristics of caplacizumab together with the available data of its efficacy and safety in the clinical setting will be analyzed. Besides, the current scenario of aTTP treatment will be provided, including the role of other innovative drugs. Expert opinion: With no doubt, caplacizumab is going to change the way we treat aTTP. In combination with standard treatment, caplacizumab can help to significantly reduce aTTP-related mortality and morbidity and could spare potential long-term consequences by minimizing the risk of exacerbation.

Severe primary refractory thrombotic thrombocytopenic purpura (TTP) in the post plasma exchange (PEX) and rituximab era.

Acute acquired thrombotic thrombocytopenic purpura (TTP) requires prompt recognition and initiation of plasma exchange (PEX) therapy and immunosuppression. When PEX fails, mortality nears 100%, making finding an effective treatment crucial. Primary refractory TTP occurs when initial therapies fail or if exacerbations occur during PEX therapy, both signifying the need for treatment intensification to achieve clinical remission. Rituximab helps treat most of the refractory TTP cases, except those that are severely refractory. A paucity of studies guiding severely refractory TTP makes management arbitrary and individualised, highlighting the value of isolated reports. We present an extremely rare case of primary refractory TTP with an insufficient platelet response to numerous types of treatments, including emerging therapies such as caplacizumab, on the background of repeated PEX and immunosuppressive therapies.

Use of double filtration plasmapheresis for the treatment of acquired thrombocytopenic thrombotic purpura.

Double filtration plasmapheresis (DFPP) could be an alternative method to simple plasma exchange plasmapheresis in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP). In a retrospective single center case series, we studied clinical presentation, management care, and prognosis of aTTP patients from our academic center treated with DFPP and IV infusion of fresh frozen plasma (FFP) between 2009 and 2018. Nine patients were included for 11 episodes. Median age was 38 years old (IQR 26-53) with 78% women. Six episodes (55%) required admission to the ICU, four of which required mechanical ventilation. Median FFP volume transfused was 35.2 mL/kg/d of session. Response was complete for nine episodes (82%). Four patients presented an early relapse, two a late relapse. Four patients died: one had an active untreated HCV infection, and two were over 80-year-old polymorbid patients. DFPP seems to be an efficient method of therapeutic plasmapheresis in TTP when combined with FFP transfusion and immunosuppressive treatments.

Graves disease-induced thrombotic thrombocytopenic purpura: a case report.

BACKGROUND: Thrombotic thrombocytopenic purpura is an autoimmune disease that carries a high mortality. Very few case reports in the literature have described a relationship between Graves disease and thrombotic thrombocytopenic purpura. We present a case of a patient with Graves disease who was found to be biochemically and clinically hyperthyroid with concurrent thrombotic thrombocytopenic purpura. CASE PRESENTATION: Our patient was a 30-year-old African American woman with a history of hypertension and a family history of Graves disease who had recently been diagnosed with hyperthyroidism and placed on methimazole. She presented to our hospital with the complaints of progressive shortness of breath and dizziness. Her vital signs were stable. On further evaluation, she was diagnosed with thrombotic thrombocytopenic purpura, depending on clinical and laboratory results, and also was found to have highly elevated free T4 and suppressed thyroid-stimulating hormone. She received multiple sessions of plasmapheresis and ultimately had a total thyroidectomy. The patient's hospital course was complicated by pneumonia and acute respiratory distress syndrome. Her platelets stabilized at approximately 50,000/µl, and her ADAMTS13 activity normalized despite multiple complications. The patient ultimately had a cardiac arrest with pulseless electrical activity and died despite multiple attempts at cardiopulmonary resuscitation. CONCLUSION: Graves disease is an uncommon trigger for the development of thrombotic thrombocytopenic purpura, and very few cases have been reported thus far. Therefore, clinicians should be aware of this association in the appropriate clinical context to comprehensively monitor hyperthyroid patients during treatment.

[Acquired thrombotic-thrombocytopenic purpura - patient management with the advent of novel therapeutic agents]. / Erworbene thrombotisch-thrombozytopenische Purpura ­ Patientenmanagement im Licht neuer Therapien.

HISTORY: A 42-year-old female patient presented with pyelonephritis. Two days later she complained of hematomas and petechia of the extremities. DIAGNOSIS/CLINICAL FINDINGS: Acquired thrombotic thrombocytopenic purpura was diagnosed. Laboratory result showed a thrombotic microangiopathy and thrombocytopenia of 8 × 10E9/l. ADAMTS13-activity was reported to be reduced and inhibitory antibodies to be present. THERAPY AND COURSE: The patient was placed on a therapy with plasma exchange, high-dose steroids, and caplacizumab based on a positive PLASMIC score. Once the diagnosis was confirmed by diminished ADAMTS13-activity and the presence of autoantibodies, rituximab was added. The patient responded well but showed persistently elevated levels of ADAMTS13-autoantibodies, which lead to an extension of Caplacizumab treatment to 58 days. DISCUSSION: Caplacizumab represents a novel effective treatment option for patients with acquired thrombocytopenic purpura. Time to treatment response as well as the risk of relapse were shown to be significantly reduced. However, persistent autoimmune activity can be demonstrated in a significant portion of the patients after the end of treatment putting them at risk for relapses. Thus, careful and frequent surveillance is required.

Expert statement on the ICU management of patients with thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is fatal in 90% of patients if left untreated and must be diagnosed early to optimize patient outcomes. However, the very low incidence of TTP is an obstacle to the development of evidence-based clinical practice recommendations, and the very wide variability in survival rates across centers may be partly ascribable to differences in management strategies due to insufficient guidance. We therefore developed an expert statement to provide trustworthy guidance about the management of critically ill patients with TTP. As strong evidence was difficult to find in the literature, consensus building among experts could not be reported for most of the items. This expert statement is timely given the recent advances in the treatment of TTP, such as the use of rituximab and of the recently licensed drug caplacizumab, whose benefits will be maximized if the other components of the management strategy follow a standardized pattern. Finally, unanswered questions are identified as topics of future research on TTP.

Patient Experience with Congenital (Hereditary) Thrombotic Thrombocytopenic Purpura: A Conceptual Framework of Symptoms and Impacts.

BACKGROUND AND OBJECTIVE: Thrombotic thrombocytopenic purpura is a rare, life-threatening disorder characterized by microangiopathic hemolytic anemia and thrombocytopenia, with variable clinical manifestations (e.g., central nervous system, renal, gastrointestinal, and cardiac effects). This study's objective was to gain an in-depth understanding of patients' experiences with the congenital form of thrombotic thrombocytopenic purpura, including the most salient symptoms and impacts associated with congenital thrombotic thrombocytopenic purpura and its treatment. METHODS: An initial conceptual model of thrombotic thrombocytopenic purpura symptoms and impacts was derived from a targeted literature review, refined by interviews with expert hematologists, and further refined by concept elicitation telephone interviews with adults with congenital thrombotic thrombocytopenic purpura in the USA. Patients reported the duration, frequency, and severity experienced for each concept, and rated level of disturbance on a minimum to maximum scale of 0-10. RESULTS: Interviews were conducted with 11 patients (mean age, 38.2 years; range 21-52 years) in three waves (n = 4, n = 4, n = 3). The most salient symptoms (reported most frequently and rated by patients as most disturbing) were fatigue, headache, bruising, joint pain, muscular pain, forgetfulness, and difficulty communicating. The most salient impacts included diminished ability to work/study, financial distress, feeling depressed, feeling anxious, and mood swings. Patients' comments reflected the pervasive nature of congenital thrombotic thrombocytopenic purpura symptoms and impacts, and unmet treatment needs. CONCLUSIONS: The final conceptual model, which includes salient symptoms and impacts of congenital thrombotic thrombocytopenic purpura and reflects the disease burden, was derived by integrating inputs from the literature review, expert opinion, and patient interviews, and will be used to develop a congenital thrombotic thrombocytopenic purpura-specific, patient-reported outcome instrument.

Scleroderma renal crisis: a review for emergency physicians.

Scleroderma renal crisis (SRC) remains a high-risk clinical presentation, and many patients require emergency department (ED) management for complications and stabilization. This narrative review provides an evidence-based summary of the current data for the emergency medicine evaluation and management of SRC. While SRC remains a rare clinical presentation, surveillance data suggest an overall incidence between 4 and 6% of patients with scleroderma. The diagnostic criteria for SRC include a new onset blood pressure > 150/85 mm Hg OR increase ≥ 20 mm Hg from baseline systolic blood pressure, along with a decline in renal function, defined as an increase serum creatinine of ≥ 10% and supportive features. There are many risk factors for SRC, including diffuse and rapidly progressive skin thickening, palpable tendon friction rubs, and new anemia or cardiac events. Critical patients should be evaluated in the resuscitation bay, and consultation with the nephrology team for appropriate patients improves patient outcomes.

Clinical pharmacology of caplacizumab for the treatment of patients with acquired thrombotic thrombocytopenic purpura.

Introduction: Caplacizumab is a humanized anti-von Willebrand Factor (vWF) Nanobody® for the treatment of acquired Thrombotic Thrombocytopenic Purpura (aTTP). Caplacizumab targets the A1-domain of vWF, inhibiting the interaction between vWF and platelets. Clinical studies conducted in aTTP patients confirmed the rapid and sustained complete suppression of the vWF activity using an initial intravenous dose of 10 mg, and a maintenance subcutaneous 10 mg daily dosing regimen, with corresponding favorable efficacy and safety profiles. Areas covered: The pharmacokinetics of caplacizumab are non-linear, characterized by a target-mediated disposition and the exposure is dependent upon drug and target concentration over time. The pharmacokinetics of caplacizumab are predictable when considering the turn-over of the circulating vWF and its modulation by the drug over time. Renal and hepatic impairment are not expected to influence the exposure to the drug, and no direct or indirect drug-drug pharmacokinetic interactions are anticipated based on the mechanism of action and the specificity of the pharmacodynamic effect of caplacizumab. Expert opinion: Caplacizumab prevents the interaction between vWF and platelets, offering a direct and rapid therapeutic intervention to stop microthrombosis. The combination of caplacizumab with plasma exchange and immunosuppression represents an important, potentially life-saving advance in the treatment of aTTP patients.