Thrombotic thrombocytopenic purpura-like syndrome associated with arcanobacterium pyogenes endocarditis in a post-transplant patient: A case report.

Systemic Arcanobacterium pyogenes is a rare bacterial infection in humans.1The diagnosis of thrombotic thrombocytopenic purpura (TTP)-like syndrome and infective endocarditis (IE) is often elusive. We report a case of TTP-like syndrome associated with A. pyogenes endocarditis in a post-allogenic transplant patient.

Shiga toxin-associated hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: distinct mechanisms of pathogenesis.

The hemolytic uremic syndrome (HUS) of childhood is, in its most common form, a non-immune microangiopathic hemolytic anemia. HUS typically follows an enteric infection with a Shiga toxin-producing Escherichia coli, usually belonging to serotype O157:H7. The antecedent infection is almost always manifested as non-bloody diarrhea. In about 80% of cases, the diarrhea becomes bloody between one and five days after the onset of diarrhea. The courses of acute gastrointestinal infections, and of HUS, in adults and children are similar. There are no convincing data that this easily recognizable form of microangiopathy is related to any inborn or acquired deficiency of ADAMTS13, and plasma therapies are not justified on either theoretical or empirical grounds. Similarly, there are no realistic animal data to support use of plasma exchange or infusion in children or adults with, or at risk for, HUS secondary to gastrointestinal infection with E. coli O157:H7. Best clinical practices involve rapid and accurate clinical and microbiological identification of infected patients, volume expansion, and support of the intestinal and extraintestinal complications that can ensue during acute enteric infection and associated HUS. Clinical clues include a sequence of events where the stool becomes bloody after a several-day interval of bloody diarrhea, considerable abdominal pain, five or more stools in the 24 h before presentation, pain on defection, and absence of fever at the time of presentation. Diagnosis should rely primarily on sorbitol MacConkey agar culture. Shiga toxin testing should not be used as the only screen to identify infected patients.

Association of Appendicitis, Helicobacter Pylori Positive Gastritis and Thrombotic Thrombocytopenic Purpura in an Adolescent.

BACKGROUND Thrombotic thrombocytopenic purpura (TTP) in children is a rare life-threatening syndrome, characterized by microangiopathic hemolytic anemia, thrombocytopenia with renal dysfunction, neurologic symptoms, and fever. TTP is usually caused by deficient activity of von Willebrand factor cleaving protease (ADAMTS13), due to either gene mutations or acquired via anti-ADAMTS13 autoantibodies. It can be triggered by bone marrow or solid organ transplantation, cardiothoracic-, abdominal-, and orthopedic surgeries, infections including very rarely Helicobacter pylori infection. CASE REPORT Here we report a case of a 16-year-old male with TTP, who presented with thrombocytopenia before an appendectomy. Seven days after surgery, our patient started to vomit, developed melena, and was admitted to our pediatric intensive care unit (PICU) with clinical presentation of shock. Gastroscopy revealed H. pylori positive hemorrhagic gastritis. The patient was treated by erythrocyte transfusions, fresh frozen plasma, human albumin, glucose-electrolyte solutions, vitamin K, platelet transfusion before implantation of central venous catheter, and antibiotics. After 36 hours, we started plasma exchange (PEX). Blood tests showed deficiency of ADAMTS13. Due to the presence of anti-ADAMTS13 autoantibodies, rituximab was administered. Due to generalized tonic-clonic seizures, he was artificially ventilated. Brain MR angiography showed small ischemic cerebro-vascular insult in the arteria cerebri media region. Despite immunosuppressive therapy and PEX, the patient did not improve completely until the H. pylori infection was eradicated. After which, he recovered completely. CONCLUSIONS We present a rare case of TTP accompanied with appendicitis and gastritis caused by H. pylori, where TTP improvement was dependent on H. pylori infection eradication.

Sporadic bloody diarrhoea-associated thrombotic thrombocytopenic purpura-haemolytic uraemic syndrome: an adult and paediatric comparison.

Although diarrhoea-associated haemolytic uremic syndrome (HUS) in children is well described, the clinical features of bloody diarrhoea-associated thrombotic thrombocytopenic purpura (TTP)-HUS in adults are not documented. Twenty-one adults, 6.5% of the 322 adults in The Oklahoma TTP-HUS Registry, 1989-2006, have presented with bloody diarrhoea. There were no case clusters. Escherichia coli O157:H7 was identified in five patients, but many patients did not have appropriate studies. The annual incidence was 0.68/10(6), 10-fold less than the incidence of diarrhoea-associated HUS in children in Oklahoma. Two (13%) of 16 patients in whom ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) was measured had <10% activity. Severe neurological abnormalities (67%) and renal failure (62%) were common; seven patients (33%) died; no survivors have relapsed. Compared to the 38 other Oklahoma Registry patients with ADAMTS13 <10%, frequency of severe neurological abnormalities and death was not different; frequency of renal failure was greater; frequency of relapse was less. Compared to 5999 children with sporadic diarrhoea-associated HUS in published reports, frequency of renal failure and relapse was not different; frequency of severe neurological abnormalities and death was greater (P < 0.05 for all differences). Awareness of the continuous occurrence of sporadic bloody diarrhoea-associated TTP-HUS in adults is important for prompt diagnosis and appropriate management.

[Haemolytic uremic syndrome and thrombotic thrombocytopenic purpura: classification based on molecular etiology and review of recent developments in diagnostics]. / A hemolitikus urémiás szindróma és a trombotikus thrombocytopeniás purpura molekuláris szemléletu klasszifikációja és diagnosztikájuknak aktuális kérdései.

Haemolytic uremic syndrome and thrombotic thrombocytopenic purpura are overlapping clinical entities based on historical classification. Recent developments in the unfolding of the pathomechanisms of these diseases resulted in the creation of a molecular etiology-based classification. Understanding of some causative relationships yielded detailed diagnostic approaches, novel therapeutic options and thorough prognostic assortment of the patients. Although haemolytic uremic syndrome and thrombotic thrombocytopenic purpura are rare diseases with poor prognosis, the precise molecular etiology-based diagnosis might properly direct the therapy of the affected patients. The current review focuses on the theoretical background and detailed description of the available diagnostic possibilities, and some practical information necessary for the interpretation of their results.

Thrombotic thrombocytopenic purpura: proposal of a new pathogenic mechanism involving Helicobacter pylori infection.

Thrombotic thrombocytopenic purpura (TTP) is a severe, occlusive, thrombotic microangiopathy characterized by a systemic platelet aggregation, organ ischemia, profound thrombocytopenia and erythrocyte fragmentation. Recent observations have documented that a deficiency of a von Willebrand factor (VWF)-cleaving protease, termed ADAMTS13, that normally cleaves hyper-reactive unusually large VWF multimers into smaller and less adhesive VWF forms, may be responsible for many cases of TTP. Multiple mutations of the ADAMTS13 gene can result in ADAMTS13 deficiency and cause congenital TTP, while autoantibodies neutralizing ADAMTS13 protease activity have been associated with acquired TTP. However, in spite of the recent progresses in the pathophysiology of TTP, many aspects of this disease remain still controversial. In this study, basing on the laboratory results of a group of eight patients with an acquired form of TTP, an alternative pathogenic mechanism for TTP involving Helicobacter pylori infection is proposed. In fact, Helicobacter pylori, which has been recently implied in the pathogenesis of idiopathic thrombocytopenic purpura (ITP), could function as a triggering factor in TTP by inducing platelet aggregation through an interaction with VWF.

Outbreak of Escherichia coli O157:H7 and Campylobacter among attendees of the Washington County Fair-New York, 1999.

September 3, 1999, the New York State Department of Health (NYSDOH) received reports of at least 10 children hospitalized with bloody diarrhea or Escherichia coli O157:H7 infection in counties near Albany, New York. All of the children had attended the Washington County Fair, which was held August 23-29, 1999; approximately 108,000 persons attended the fair during that week. Subsequently, fair attendees infected with Campylobacter jejuni also were identified. An ongoing investigation includes heightened case-finding efforts, epidemiologic and laboratory studies, and an environmental investigation of the Washington County fairgrounds. This report presents the preliminary findings implicating contaminated well water.

Gnotobiotic piglets develop thrombotic microangiopathy after oral infection with enterohemorrhagic Escherichia coli.

Oral infection with enterohemorrhagic Escherichia coli (EHEC) may cause severe enteritis, followed in up to 10% of cases by an extraintestinal complication, the hemolytic uremic syndrome (HUS). HUS is characterized by a triad of symptoms: anemia, thrombocytopenia, and acute renalfailure due to thrombotic microangiopathy. EHEC produces several virulence factors, among which a family of phage-encoded cytotoxins, called Shiga toxin 1 and Shiga toxin 2, seems to be most important. However, since an appropriate animal model is not available, pathogenicity of these emerging enteric pathogens is still poorly understood. Germ-free gnotobiotic piglets infected orally with an O1577:H7 or an O26:H11 EHEC wild-type isolate, both producing Shiga toxin 2, developed intestinal and extraintestinal manifestations of EHEC disease, including thrombotic microangiopathy in the kidneys, the morphologic hallmark of HUS in humans. Thus, gnotobiotic piglets are suitable to further study the pathophysiology of EHEC-induced HUS. It can be expected that data obtainedfrom this animal model will improve our current standard of knowledge about this emerging infectious disease.

Infectious diseases as a trigger in thrombotic microangiopathies in intensive care unit (ICU) patients?

OBJECTIVE: Thrombotic microangiopathy (TMA) has been associated with a large number of underlying diseases. We conducted a descriptive, retrospective study including all TMA adult patients admitted to our ICU, with a particular interest in infectious episodes as a trigger of TMA. PATIENTS: All adult patients (30) with a diagnosis of TMA admitted to the medical ICU at Saint-Louis Hospital (Paris, France) between 1992 and 1998 were retrospectively included. METHODS: All patients with clinical and microbiological evidence of bacterial infection were treated with intravenous antibiotics. The specific treatment of TMA consisted in solvent/detergent-treated plasma administration by plasma exchange or high volume plasma infusion (30 ml/kg per day) in fractionated doses. RESULTS: Among the 30 adult patients studied, TMA in 16 (53%) was associated with microbiologically documented infection. An acute infection was found in 8/9 patients with an HIV-related TMA, in 2/6 patients with a systemic lupus erythematosus (SLE)-related TMA and in 3/6 patients with TMA associated with other disorders. In three patients, an acute infectious disease was the only cause associated with the TMA. Four other patients had clinical manifestations suggesting an infection process but without bacteriological documentation. Escherichia coli was isolated in 7/16 cases and verotoxin was found in the stools of two other patients. All patients were treated with plasma administration and those with evidence of infection were systematically and intensively treated with antibiotics. Eventually 8 patients died (27%), 20 (67%) reached complete remission and 2 partial remission. CONCLUSION: Bacterial infections are commonly observed amongst TMA patients hospitalized in ICUs and may act as a trigger of this disease. Screening for infection is a requirement in patients with TMA, either idiopathic or associated with other conditions.

Possibilities and limits of treatment in patients with thrombotic thrombocytopenic purpura.

Results of treatment of 18 patients fulfilling the criteria for TTP are presented. Thrombocytopenia was present in all patients (100%). Sixteen of the 18 patients (88.8%) had mental status changes, and seven of the 18 patients (38.8%) had renal impairment. One patient had a secondary type of TTP, caused by non-Hodgkin's lymphoma of the large intestine (that was diagnosed later) and was excluded from the study. Immunosuppresive therapy with steroids, plasma exchange and replacement of removed volume with fresh frozen plasma in a dosage of 25 ml/kg body weight resulted in a statistically significant increase of platelet count (P = 0.00222), and a significant improvement in consciousness defined by increased GCS after 2 weeks (P = 0.00222). In two patients renal function recovered, and in one of them hemodialysis was no longer needed. This improvement in a small group of patients had no statistical significance. TTP recurred in seven patients. High doses of steroids caused serious side effects in two patients: in one patient, steroid diabetes, and in the other one, intestinal perforation.

The management of VTEC O157 infection.

VTEC O157 infections, although showing a relentless rise in incidence over the last decade, only account for less than 10% of total food poisoning notifications in the UK. Despite this, the propensity for this infection to cause the serious and life-threatening clinical complications of haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopaenic purpura (TTP), in a significant proportion (2-15%) of sufferers, highlights the need to focus on it both epidemiologically and clinically. The mortality rate of these complications (3-17% and up to 30% in outbreaks) adds urgency to this consideration. The pathogenesis and epidemiology of the illness caused by VTEC O157 is now well described, allowing the potential for appropriate intervention in outbreak and individual clinical management. The presence or absence of symptoms, e.g. bloody diarrhoea, fever, vomiting, in VTEC O157 infections compared with other causes of gastroenteritis may allow some selection of cases for more intensive management. Age (< 15, > 65 years), clinical hypochlorhydria. and a short incubation period have been associated with complication (HUS/TTP) development. Antibiotic therapy in the pre-infection period may predispose to complication development and there is evidence that it may increase complications if used in the management of acute illness. Laboratory markers such as early neutrophil leukocytosis have been shown both to correlate with VTEC O157 infection and to predict complications in central Scotland and Japan. The serum albumin and the C-reactive protein may act as additional markers for HUS development. Laboratory markers may be differentiated into those predicting HUS/TTP and those useful in monitoring its development. A scheme for clinical management of affected cases is presented to allow the attending clinician to select cases that may benefit from further intervention to prevent or treat complications.

Southwestern Internal Medicine Conference: Shiga-like toxins in hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura.

The majority of cases of hemolytic-uremic syndrome and a smaller proportion of cases of thrombotic thrombocytopenic purpura have recently been shown to result from a toxin produced by enteric bacteria, referred to as verotoxin, or Shiga-like toxin. The predominant toxin-producing bacterial strain in North America is E. coli O157:H7, which causes hemorrhagic colitis in humans after ingestion of contaminated meat. The toxin is believed to gain entry to the circulation from the bowel wall; it then binds to specific glycolipid receptors abundant on renal vascular endothelial cells. The toxin inactivates ribosomes inside the cells, thereby killing them and producing the clinical manifestations of hemolytic-uremic syndrome. Recognition of the etiology of hemolytic-uremic syndrome may lead to better prospects for prevention and treatment.

L-arginine as a therapeutic approach for the verotoxigenic Escherichia coli-induced hemolytic uremic syndrome and thrombotic thrombocytopenic purpura.

Infection with verotoxigenic Escherichia coli, mainly strain O157:H7, has been incriminated in the cause of the hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Both syndromes, which cause serious problems in children and elderly patients, are not readily treated. Conventional treatment with antibiotics has been reported to not only stimulate bacteria to increase toxin production, but also to enhance its release from the cell. This in turn increases the severity of the disease. An alternative approach to the control of the disease would involve treatment with the amino acid L-arginine, in high amounts through total parenteral nutrition. L-arginine will generate high amounts of nitric oxide which will decrease platelet aggregation and increase vasodilation. Both effects will decrease the development of the tubular occlusion and the accompanied hypertension. In summary, we hypothesize that L-arginine can be used to control two diseases caused by E. coli O157:H7.

[Thrombotic thrombocytopenic purpura in a child with low ADAMTS13 enzyme level]. / Trombotisk trombocytopenisk purpura hos et barn med lavt ADAMTS13-enzymniveau.

Thrombotic thrombocytopenic purpura (TTP) is a rare condition, but important to consider in case of thrombocytopenia and haemolysis. It is imperative to proceed with the correct treatment, in order to ensure a satisfactory outcome. TTP is either acquired or idiopathic. This case report shows that a 14-year-old boy has acquired TTP due to an infection with Campylobacter jejuni and Samonella szentes. Plasma exchange plays an essential role in the treatment of TTP.

Shiga toxins and the pathophysiology of hemolytic uremic syndrome in humans and animals.

Food-borne diseases are estimated at 76 million illnesses and 5000 deaths every year in the United States with the greatest burden on young children, the elderly and immunocompromised populations. The impact of efficient food distribution systems and a truly global food supply ensures that outbreaks, previously sporadic and contained locally, are far more widespread and emerging pathogens have far more frequent infection opportunities. Enterohemorrhagic E. coli is an emerging food- and water-borne pathogen family whose Shiga-like toxins induce painful hemorrhagic colitis with potentially lethal complications of hemolytic uremic syndrome (HUS). The clinical manifestations of Shiga toxin-induced HUS overlap with other related syndromes yet molecular mechanisms differ considerably. As discussed herein, understanding these differences and the novel properties of the toxins is imperative for clinical management decisions, design of appropriate animal models, and choices of adjunctive therapeutics. The emergence of new strains with rapidly aggressive virulence makes clinical and research initiatives in this field a high public health priority.

Capnocytophaga canimorsus infection presenting with complete splenic infarction and thrombotic thrombocytopenic purpura: a case report.

BACKGROUND: Animal bites are typically harmless, but in rare cases infections introduced by such bites can be fatal. Capnocytophaga canimorsus, found in the normal oral flora of dogs, has the potential to cause conditions ranging from minor cellulitis to fatal sepsis. The tendency of C. canimorsus infections to present with varied symptoms, the organism's fastidious nature, and difficulty of culturing make this a challenging diagnosis. Rarely, bacterial cytotoxins such as those produced by C. canimorsus may act as causative agents of TTP, further complicating the diagnosis. Early recognition is crucial for survival, and the variability of presentation must be appreciated. We present the first known case of C. canimorsus infection resulting in TTP that initially presented as splenic infarction. CASE PRESENTATION: 72-year-old Caucasian male presented with a four-day history of abdominal pain, nausea, vomiting, diarrhea, and intermittent confusion. On presentation, vital signs were stable and the patient was afebrile. Physical examination was unremarkable apart from petechiae on the inner left thigh, and extreme diffuse abdominal pain to palpation and percussion along with positive rebound tenderness. Initial investigations revealed leukocytosis with left shift and thrombocytopenia, but normal liver enzymes, cardiac enzymes, lipase, INR and PTT. Abdominal CT demonstrated a non-enhancing spleen and hemoperitoneum, suggesting complete splenic infarction. Although the patient remained afebrile, he continued deteriorating over the next two days with worsening thrombocytopenia. After becoming febrile, he developed microangiopathic hemolytic anemia and hemodynamic instability, and soon after was intubated due to hypoxic respiratory failure and decreased consciousness. Plasma exchange was initiated but subsequently stopped when positive blood cultures grew a gram-negative organism. The patient progressively improved following therapy with piperacillin-tazobactam, which was switched to imipenem, then meropenem when Capnocytophaga was identified. CONCLUSIONS: There is a common misconception amongst practitioners that the presence of systemic infection excludes the possibility of TTP and vice versa. This case emphasizes that TTP may occur secondary to a systemic infection, thereby allowing the two processes to coexist. It is important to maintain a wide differential when considering the diagnosis of either TTP or C. canimorsus infection since delays in treatment may have fatal consequences.