Thrombotic Thrombocytopenic Purpura

Autoantibodies neutralizing human ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motif), the metalloprotease that physiologically cleaves von Willebrand factor, are a major cause of severe deficiency of the protease and of acquired thrombotic ...

Many foodborne diseases are associated with consumption of meat and poultry. Some pathogens were not previously known (new pathogens), others have newly arisen as foodborne (emerging pathogens), and others have become more potent or associated with other products (evolving pathogens). Many of these pathogens may cause severe illness, besides gastroenteritis. Campylobacter jejuni is a leading cause of food-associated bacterial illness; Campylobacter jejuni O:19 and other serotypes are common etiological agents of Guillain–Barré syndrome, a neuropathy due to autoimmune response. Salmonella Typhimurium DT104 and other serotypes have been found to be multi-drug resistant; salmonellosis may lead to chronic reactive arthritis. Many outbreaks of enterohemorrhagic Escherichia coli have been associated with consumption of undercooked contaminated ground beef; complication may occur (e.g., hemolytic uremic syndrome and thrombotic thrombocytopenic purpura). Listeria monocytogenes is ubiquitous; listeriosis is of major public health concern because of the severity and non-enteric nature of the disease (meningitis or meningoencephalitis, septicemia, and abortion) and its ability to multiply at refrigeration temperature. Arcobacter butzleri is a potential foodborne pathogen, and has been isolated from raw poultry, meat, and meat products; but its role in causing human illness is not fully understood. Mycobacterium avium subsp. paratuberculosis can be transmitted by ingestion of raw and processed meats; the organism may contribute to Crohn’s disease, a chronic intestinal enteritis. Beef, pork, lamb, and/or poultry have been reported as sources of infection for the abovementioned organisms but have not been generally associated with disease outbreaks of some of the pathogens.

Congenital thrombotic thrombocytopenic purpura (TTP) (also known as Upshaw-Schulman syndrome, USS) is a rare, life-threatening disease characterized by thrombocytopenia and microangiopathic hemolytic anemia, associated with the deficiency of the von Willebrand factor-cleaving protease (ADAMTS13) due to mutations in the corresponding gene. The spectrum of clinical phenotype in congenital TTP is wide, encompassing neonatal-onset disease and adult-onset disease, forms with a single disease episode and chronic-relapsing forms. We review ADAMTS13 gene variants associated with inherited ADAMTS13 deficiency and congenital TTP. To date, 76 mutations of ADAMTS13 are reported in the literature. Missense mutations, which constitute nearly 60% of ADAMTS13 mutations, preferentially localize in the 5′-half of the gene encoding the N-terminal half of the protein, where the domains that are indispensable for ADAMTS13 catalytic function are situated. In vitro expression studies in cell cultures have shown that defects in protein secretion and catalytic activity are the main mechanisms responsible for the deficiency of ADAMTS13 in congenital TTP patients. Even if data from the literature suggest the existence of genotype–phenotype correlations, a clear relationship between the type and the effect of ADAMTS13 genetic defects with disease manifestations remains to be established. Hum Mutat 30:1–9, 2009. © 2009 Wiley-Liss, Inc.

Abstract:  Plasmapheresis (PP) is widely known as the standard therapy for thrombotic thrombocytopenic purpura (TTP). Citrate is used as an anticoagulant in fresh frozen plasma, and the large amount of citrate infused during PP induces metabolic alkalosis. A 29-year-old woman was diagnosed with TTP associated with systemic lupus erythematosus, and was treated by daily PP in addition to a steroid, an immunosuppressant, vincristine, and cyclophosphamide. Uncompensated alkalosis caused by a combination of metabolic and respiratory alkalosis developed after artificial ventilation was discontinued. Her metabolic status improved after controlling her respiratory status and the activity of the TTP. Metabolic alkalosis is a common complication in TTP patients treated by frequent PP, but several factors that affect metabolic status may aggravate the alkalosis and induce uncompensated alkalosis.

Severe deficiency in the von Willebrand factor-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) because of mutations in the ADAMTS13 gene can lead to acute episodes of congenital thrombotic thrombocytopenic purpura (TTP), requiring prompt treatment. Current treatment consists of therapeutic or prophylactic infusions of fresh frozen plasma. However, lifelong treatment with plasma products is a stressful therapy for TTP patients. Here, we describe the use of the nonviral sleeping beauty (SB) transposon system as a gene therapeutic approach to realize lifelong expression of ADAMTS13 and subsequent protection against congenital TTP. We demonstrated that hydrodynamic tail vein injection of the SB100X system expressing murine ADAMTS13 in Adamts13(-/-) mice resulted in long-term expression of supraphysiological levels of transgene ADAMTS13 over a period of 25 weeks. Stably expressed ADAMTS13 efficiently removed the prothrombotic u...

Thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (TTP/HUS) is a multisystem disorder characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, renal function abnormalities, and fever. Coexistence of TTP/HUS and adult onset Still’s disease (ASD) is extremely rare. We report the case of a 46-year-old woman who presented with fever, arthritis, myalgias, petechia on skin and confusion five years after the onset of ASD. Thrombocytopenia, renal failure, marked elevation lactate dehydrogenase, and red cell fragmentation on peripheral blood smear were observed. We made a diagnosis of TTP/HUS associated with ASD, according to physical examination and characteristic laboratory data. She recovered from the TTP/HUS following daily sessions of therapeutic plasma exchange with fresh frozen plasma replacement and glucocorticoid therapy. Awareness of the possible development of TTP/HUS in ASD is important for early diagnosis and treatment.