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.

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.

Thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP; also known as Moschcowitz disease) is characterized by the concomitant occurrence of often severe thrombocytopenia, microangiopathic haemolytic anaemia and a variable degree of ischaemic organ damage, particularly affecting the brain, heart and kidneys. Acute TTP was almost universally fatal until the introduction of plasma therapy, which improved survival from <10% to 80-90%. However, patients who survive an acute episode are at high risk of relapse and of long-term morbidity. A timely diagnosis is vital but challenging, as TTP shares symptoms and clinical presentation with numerous conditions, including, for example, haemolytic uraemic syndrome and other thrombotic microangiopathies. The underlying pathophysiology is a severe deficiency of the activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13), the protease that cleaves von Willebrand factor (vWF) multimeric strings. Ultra-large vWF strings remain uncleaved after endothelial cell secretion and anchorage, bind to platelets and form microthrombi, leading to the clinical manifestations of TTP. Congenital TTP (Upshaw-Schulman syndrome) is the result of homozygous or compound heterozygous mutations in ADAMTS13, whereas acquired TTP is an autoimmune disorder caused by circulating anti-ADAMTS13 autoantibodies, which inhibit the enzyme or increase its clearance. Consequently, immunosuppressive drugs, such as corticosteroids and often rituximab, supplement plasma exchange therapy in patients with acquired TTP.

Epidemiology and pathophysiology of adulthood-onset thrombotic microangiopathy with severe ADAMTS13 deficiency (thrombotic thrombocytopenic purpura): a cross-sectional analysis of the French national registry for thrombotic microangiopathy.

BACKGROUND: Thrombotic thrombocytopenic purpura is a thrombotic microangiopathy related to a severe deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13; activity <10%). We aimed to investigate the association between mechanisms for ADAMTS13 deficiency and the epidemiology and pathophysiology of thrombotic thrombocytopenic purpura at initial presentation. METHODS: Between Jan 1, 1999, and Dec 31, 2013, we did a cross-sectional analysis of the French national registry for thrombotic microangiopathy to identify all patients with adult-onset thrombotic microangiopathy (first episode after age 18 years) who had severe ADAMTS13 deficiency at presentation. ADAMTS13 activity, anti-ADAMTS13 IgG, and ADAMTS13 gene mutations were investigated by a central laboratory. We collected patients' clinical data for correlation with their ADAMTS13 phenotype and genotype. We used logistic regression analysis to identify variables significantly associated with idiopathic thrombotic thrombocytopenic purpura, as measured by estimated odds ratios (ORs) and 95% CIs. This study is registered with ClinicalTrials.gov, number NCT00426686. FINDINGS: We enrolled 939 patients with adult-onset thrombotic thrombocytopenic purpura, of whom 772 (82%) patients had available data and samples at presentation and comprised the cohort of interest. The prevalence of thrombotic thrombocytopenic purpura in France was 13 cases per million people. At presentation, 378 (49%) patients had idiopathic thrombotic thrombocytopenic purpura, whereas 394 (51%) patients had disease associated with miscellaneous clinical situations (infections, autoimmunity, pregnancy, cancer, organ transplantation, and drugs). Pathophysiologically, three distinct forms of thrombotic thrombocytopenic purpura were observed: 585 (75%) patients had autoimmune disease with anti-ADAMTS13 IgG, 166 (22%) patients had acquired disease of unknown cause and 21 (3%) patients had inherited disease (Upshaw-Schulman syndrome) with mutations of the ADAMTS13 gene. Idiopathic thrombotic thrombocytopenic purpura were mainly autoimmune (345 [91%] cases), whereas non-idiopathic diseases were heterogeneous, including a high rate of unexplained mechanisms for ADAMTS13 deficiency (133 [34%] cases). Obstetrical thrombotic thrombocytopenic purpura cases (n=62) were specifically remarkable because of the high rate of patients with Upshaw-Schulman syndrome (21 [34%] patients). INTERPRETATION: Our study shows that thrombotic thrombocytopenic purpura is a heterogeneous syndrome, and that features of the disease at presentation are strongly associated with the mechanisms of ADAMTS13 deficiency. In addition to mechanistic insight, our findings could have implications for the initial therapeutic management of patients with this disorder. FUNDING: Assistance Publique-Hôpitaux de Paris.

N-Acetylcysteine for Relapsing Thrombotic Thrombocytopenic Purpura: More Evidence of a Promising Drug.

Thrombotic thrombocytopenic purpura (TTP) is a microangiopatic thrombotic state associated with a deficiency on the cleavage function of the Von Willebrand factor polymers by a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13. We report a patient with relapsing TTP successfully treated with N-acetylcysteine (NAC) after failure of plasma exchange (PE) with steroids, rituximab, cyclophosphamide, vincristine, and azathioprine. A 51-year-old male who had an altered mental status while he was on rehabilitation for a previously treated TTP with a subsequent neurologic deficit. He was treated 7 days ago with PE plus steroids and subsequently discharged to our facility for rehabilitation. He was found to have a platelet level of 153,000/mm, hemoglobin decreased from 9.2 to 6.2 g/dL, creatinine raised from 1.0 to 2.4 mg/dL, and the peripheral smear showed schistocytes. A brain computed tomography showed a subacute infarction in the left frontal lobe and an abdominal-pelvic computed tomography disclosed a retroperitoneal hematoma. PE and steroids were started for 14 days. On day 15th, rituximab was added weekly for 10 cycles. A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 activity level was 95% without platelet count improvement. We started cyclophosphamide, then vincristine, and finally azathioprine. His platelet were maintained above 150,000/mm for a few days. He had several episodes of sepsis after every chemotherapeutic drug. On day 135th, NAC was commenced at 150 mg/kg for 10 days along with PE and low-dose steroids for 10 days. Complete recover of platelet count was achieved and the patient was successfully discharged. Relapsing TTP is often difficult to manage and may last longer than expected carrying several comorbidities and complications. PE plus steroids are the mainstay of TTP treatment and Rituximab is the drug of choice after they have failed. The patient had a complete remission after NAC therapy. Hence, NAC likely can be considered an earlier choice of treatment after rituximab, before the use of chemotherapeutic agents, considering its toxic and adverse effects.

Malignant Hypertension and Thrombotic Thrombocytopenic Purpura: False Friends.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare hematologic disorder resulting in hemolysis of red blood cells, consumption of platelets, and occlusion of microvasculature. Malignant hypertension is the clinical syndrome of severe elevations in blood pressure and funduscopic hypertensive retinopathy, including bilateral flame-shaped hemorrhage and papilledema. CASE REPORT: We describe the case of a 63-year-old man who presented with features of TTP and malignant hypertension treated with plasma exchange and developing end-stage renal disease. CONCLUSIONS: Given the diagnostic uncertainty at presentation, clinicians should quickly intervene to control hypertension and institute plasma exchange as needed.

Scleroderma renal crisis or thrombotic thrombocytopenic purpura: seeing through the masquerade.

SCLERODERMA: renal crisis (SRC), a somewhat rare but serious complication of systemic scleroderma, is one of only a few known rheumatologic emergencies; it presents in as many as 10% of patients with scleroderma. Before the use of angiotensin converting enzyme (ACE) inhibitors to treat SRC, the mortality rate for SRC was extremely high-as much as 90% after 1 year. However, the mortality rate has significantly improved with the early and aggressive use of ACE inhibitors. SRC typically includes acute renal failure and accelerated hypertension. Patients may report headache, changes in vision, fever, dyspnea, and encephalopathy. Laboratory study results can show elevated creatinine levels, thrombocytopenia, and microangiopathic hemolytic anemia (MAHA) with schistocytes on blood smear. Given this clinical and laboratory presentation, SRC can easily be mistaken for TTP in clinical practice, as we demonstrate in 2 presentations of similar cases of SRC, the first in a 36-year-old Caucasian woman and the second in a 54-year-old Caucasian woman. In both cases, SRC masqueraded as TTP, and both patients were almost mistakenly treated for TTP until the clinical picture changed and certain laboratory test and kidney biopsy results confirmed otherwise.

Gemcitabine-associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.

A patient being treated for metastatic adenocarcinoma of the pancreas presents to the clinic for a routine appointment. A complete blood count reveals hemoglobin of 6.5 g/dl and a platelet count of 30,000 K/mm3 thought to be from the last of many doses of gemcitabine. On assessment, the only complaint was fatigue with no evidence of bleeding or other abnormal physical findings other than pallor. Past medical history includes hypertension managed with three antihypertensive agents. Additional laboratory tests reveal elevated blood urea nitrogen (69 mg/dl), creatinine (2.76 mg/dl), and lactic dehydrogenase (LDH), was well as indirect bilirubin (2.1 mg/dl). The patient is admitted and transfused with packed red blood cells (pRBCs). The next day, the platelet count drops to 9,000 K/mm3 and the hemoglobin increases, appropriately, to 8.9 g/dl. Urinalysis is positive for hemoglobin (+ 3). The peripheral blood smear is positive for schistocytes (fragmented RBCs). A pheresis catheter is placed after the patient was evaluated by a hematologist and a nephrologist. A presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP) with hemolytic uremic syndrome (HUS) was made.

Pathology of renal diseases associated with dysfunction of the alternative pathway of complement: C3 glomerulopathy and atypical hemolytic uremic syndrome (aHUS).

Dysfunction of the alternative pathway of complement in the fluid phase results in deposition of complement factors in the renal glomeruli. This results in glomerular injury and an ensuing proliferative response. The term "C3 glomerulopathy" is used to define such an entity. It includes both C3 glomerulonephritis and dense deposit disease (DDD). Both C3 glomerulonephritis and DDD are characterized by a proliferative glomerulonephritis and bright glomerular C3 mesangial and capillary wall staining with the absence or scant staining for immunoglobulins (Ig). The two conditions are distinguished based on electron microscopy findings: mesangial and capillary wall deposits are noted in C3 glomerulonephritis, while ribbon-shaped dense osmiophilic intramembranous and mesangial deposits are noted in DDD. On the contrary, uncontrolled activation of the alternative pathway of complement on endothelial cell surface results in endothelial injury with an ensuing thrombotic microangiopathy, termed atypical hemolytic uremic syndrome (aHUS). Kidney biopsy in aHUS is often indistinguishable from other forms of thrombotic microangiopathy including enterohemorrhagic Escherichia coli-induced HUS and thrombotic thrombocytopenic purpura and shows thrombi in glomerular capillaries, mesangiolysis, and endothelial injury as evidenced by swelling and double contour formation along the glomerular capillary walls, with negative immunofluorescence studies for Ig and complement factors and no deposits on electron microscopy.

von Willebrand factor: more than a regulator of hemostasis and thrombosis.

von Willebrand factor (vWF) was first identified as an adhesive glycoprotein involved in hemostasis by Zimmermann in 1971. Since then, vWF has been shown to play a vital role in platelet adhesion, platelet binding to collagen and factor VIII protection. Recent studies have implicated vWF as a regulator of angiogenesis, smooth muscle cell proliferation, tumor cell metastasis and crosstalk in the immune system. In this review, we will discuss the aspects of vWF structure that facilitate its biological effects and speculate on its newly discovered and hypothesized roles in the pathogenesis of several diseases.

Thrombotic thrombocytopenic purpura: a hematological emergency.

BACKGROUND: Thrombotic thrombocytopenic purpura is a hematological emergency and diagnostic challenge. The critical determinant of outcome is timely diagnosis and treatment. OBJECTIVES: Describe the pathophysiology, presentation, diagnosis, and treatment of thrombotic thrombocytopenic purpura. DISCUSSION: Thrombotic thrombocytopenic purpura has a varied presentation and a tendency to mimic several disorders. However, it may be at least provisionally diagnosed in the patient with thrombocytopenia and microangiopathic hemolytic anemia without alternate cause. The mainstay of treatment is immediate plasma exchange to be repeated until platelet count is stabilized. Adjuvant therapies include corticosteroids, rituximab, and cyclosporine. CONCLUSION: It is essential for the emergency physician to be aware of thrombotic thrombocytopenic purpura's range of presentations, diagnostic criteria, and treatment.

Sunitinib-induced microangiopathic hemolytic anemia with fatal outcome.

Sunitinib, a new vascular endothelial growth factor receptor inhibitor, has demonstrated activity in renal cell carcinoma and is now widely used in the palliative treatment of patients with metastatic renal cell carcinoma. It is generally well tolerated but has been associated with a low incidence of grade 3 and 4 toxicities including fatigue, diarrhea, anorexia, mucositis, skin toxicity, immune thrombocytopenic purpura, hypertension, hypothyroidism, cytopenias, and decreased cardiac ejection fraction. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a rare condition that is severe and may be fatal. Several medications have been implicated in causing TTP-HUS including clopidogrel, mitomycin C, cisplatin. In this report, we describe a case of atypical HUS-microangiopathic hemolytic anemia during treatment with sunitinib in a patient with metastatic renal cell carcinoma. To our knowledge, this is the fourth case of microangiopathic hemolytic anemia associated with sunitinib described in the literature and the first case with fatal outcome despite treatment with plasmapheresis, dialysis, and withdrawal of sunitinib.

Advances in our understanding of the pathogenesis of glomerular thrombotic microangiopathy.

Glomerular thrombotic microangiopathy is a hallmark feature of haemolytic uraemic syndrome, the leading cause of acute renal failure in childhood. This paper is a review of the different mechanistic pathways that lead to this histological picture in the kidney. It will focus on atypical HUS and complement dysregulation, but will also highlight some other recent advances in our understanding of this condition, including the potential role of the molecule vascular endothelial growth factor-A (VEGF-A).

Thrombotic microangiopathy: new insights.

PURPOSE OF REVIEW: In the following study new aspects and insights into the epidemiology, pathogenesis and typical morphology of kidney involvement in thrombotic microangiopathy (TMA) are discussed. TMA comprises a spectrum of microvascular thrombosis syndromes associated with multiple pathogenetic factors, that is, typical and atypical haemolytic uraemic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), malignant hypertension, drugs or systemic autoimmune diseases or antibody-mediated rejection. RECENT FINDINGS: The present article will put particular emphasis on new pathophysiological insights into the development of TMA in the various settings. In addition, new options in the therapeutic management of TMA in atypical HUS are discussed. The pathogenesis of TMA in atypical HUS primarily involves hereditary or acquired deficiencies and disturbances of the complement system. Eculizumab is a promising new therapeutic option that has been discovered recently. SUMMARY: In HUS/TTP the kidney shows characteristic vascular changes due to endothelial damage, that is, TMA, which should be clinically and morphologically differentiated from other diseases. Recent genetic and molecular studies have shed more light on the pathogenesis of TMA in atypical HUS, that is, disturbances of various aspects of the complement system, and in TTP, that is, von Willebrand factor regulation by ADAMTS13, which are also helpful in the differential diagnosis.