Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombotic thrombocytopenic purpura (TTP) is characterized by widespread occluding and persistent microthrombotic lesions. Evidence for both endothelial damage and primary platelet aggregation as possible pathogenetic mechanisms has been produced. Persistence of microthrombi has not been explained satisfactorily. In patients with TTP we studied plasma fibrinolysis and protein C. Tissue plasminogen activator (t-PA) activity levels, measured functionally, were low or unmeasurable in 11 of 12 patients; t-PA antigen levels, measured immunochemically, were normal in all six observed. The level of potent inhibitor of plasminogen activation directed against both t-PA and urokinase was elevated significantly in all 12, whereas the alpha 2-antiplasmin level was elevated in only two. Protein C antigen levels were low in three of six patients observed. Fibrinolysis levels in patients in remission did not differ from those in patients with acute disease. Plasma exchange resulted in temporary reversal of the abnormalities, but achievement of clinical remission was not associated with permanent normalization of fibrinolysis. Inasmuch as all 12 patients had severely depressed fibrinolytic mechanisms it is possible that a defect in the fibrin-clearing system permits thrombus formation to occur and proceed in an unchallenged fashion, thereby contributing to the complex events leading to arterial ischemia in vital organs.
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PMID:Fibrinolysis in health and disease: abnormal levels of plasminogen activator, plasminogen activator inhibitor, and protein C in thrombotic thrombocytopenic purpura. 243 36

Pathogenic mechanisms of renal injury by thrombotic microangiopathies present a challenge to the multidisciplinary team caring for a patient with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS). First recognized 77 years ago as a rare disorder characterized by reversible platelet aggregation in the microcirculation causing ischemia in various organs, the prognosis was always fatal. In the past 20 years, due to effective treatment with plasma exchange therapy, there has been a decline in the mortality rate to 10-20%. The classic pentad of symptoms of TPP-HUS include thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, fever, and renal impairment. Frequency of TTP-HUS appears to be increasing. Due to the urgent need for a diagnosis, sufficient diagnostic criteria for TTP-HUS are currently thrombocytopenia and microangiopathic hemolytic anemia in the absence of another apparent cause. It is imperative to have a solid understanding of the pathophysiology and current standards of practice of TTP-HUS in order to facilitate positive patient outcomes in this unique group of patients.
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PMID:Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: pathophysiology and management. 1199 52

Thrombotic microangiopathies (TMA) encompass various severe diseases characterized by microangiopathic hemolytic anemia and peripheral thrombocytopenia, associated with fever, neurological signs and renal involvement. Microvascular thrombosis is the typical lesion, and results in tissue ischemia. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are the two most classical forms. These two entities are clinically and histopathologically closely related. There is a body of evidence suggesting that endothelial cell injury is the initial event in TTP and HUS, and that it may be related to a large number of triggering factors, such as infection, connective tissue disease, drugs, cancer and chemotherapy, transplantation, and pregnancy. Endothelial cell injury enhances the release of ultra large forms of von Willebrand factor (ULvWF) multimers and other prothrombotic agents, such as plasminogen activator inhibitor and platelet activating factor, whereas it decreases the release of prostaglandin-I2, a strong inhibitor of platelet aggregation. Recently however, it has been shown that TTP and HUS were pathophysiologically distinct. Actually, TTP is associated with a deficiency in von Willebrand factor-cleaving protease, an enzyme involved in cleavage of ULvWF into circulating 200 kDa and 350 kDa fragments. This deficiency may be either congenital or acquired, and then related to an IgG inhibitory autoantibody. This protease deficiency may account for the high amounts of plasmatic ULvWF in TTP patients. In HUS, vWF-cleaving protease activity is found normal. HUS encompasses two distinct entities. Epidemic, or diarrhea-associated HUS, is associated with verotoxin or Shiga toxin-associated enterobacteriaceae. These toxins are directly responsible for endothelial cell injury. Sporadic HUS (also termed atypical HUS in children) is closely related to TTP, and shares the same triggering factors. Familial HUS has been associated in some cases with hypocomplementemia and factor H dysfunction, the pathophysiological role of which remains unclear. The study of the different triggering factors and predisposing factors may be useful to define different subsets of TMA, that may be characterized by their course and prognosis.
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PMID:[Pathophysiology of thrombotic microangiopathies: current understanding]. 1221 98

The term thrombotic microangiopathy (TMA) encompasses syndromes of thrombocytopenia, microangiopathic haemolytic anaemia, neurologic deficits, renal dysfunction and variable signs of organ impairment. Childhood cases of TMA with predominant renal failure are usually referred as Haemolytic Uremic Syndrome (HUS), and adult cases with major neurological involvement as Thrombotic Thrombocytopenic Purpura (TTP). Exotoxins, produced in most cases by E. Coli O 157:H7, have been related to diarrhea associated HUS(D + HUS). Anticancer (mitomycin), immunosuppressive drugs (cyclosporin, tacrolimus and OKT3) and as well as some antiplatelet agents (ticlopidine, clopidrogel) have been associated with both HUS and TTP. Defective factor H or vWF protease activity have been found with familiar and recurrent forms. Endothelial damage and dysfunction is most likely the initial event of the pathogenic process that eventually leads to platelet aggregation, microvascular thrombosis and tissue ischemia. TMA may occur de novo in the native kidneys of patients who received a non-kidney transplant or in the transplanted kidney of patients who progressed to ESRD because of a disease other than HUS. Calcineurin inhibitors and vascular rejection are most often involved in these cases. The disease may also recur on the transplanted kidney in patients who progressed to ESRD because of HUS/TTP. The risk of postransplant recurrence is negligible for D + HUS but is close to 100% in familial/recurrent forms associated with low C3 and decreased factor H bioavailability or activity. Withdrawal or treatment of precipitating factors are the most effective approach. Plasma therapy is usually attempted with the rationale to limit the microangiopathic process, but its efficacy for improving graft survival is unproven. The outcome of recurrent forms is almost invariably poor.
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PMID:Thrombotic microangiopathy in renal transplantation. 1222 1

Thrombotic microangiopathy is a rare disease that can be induced and precipitated by pregnancy, and is associated with high maternal and fetal morbidity and mortality. It results from abnormal intravascular platelet aggregation that leads to transient ischemia in various organs, including the central nervous system, kidneys and placenta. Plasma exchange is the most widely accepted method of treatment for this condition. Delayed diagnosis is the main reason for morbidity and mortality, and results from difficulty in differentiating thrombotic microangiopathy from other obstetric emergencies. We report two cases of thrombotic microangiopathy that occurred antepartum and postpartum, respectively. The first patient was a 33-year-old woman who had two previous episodes of intrauterine fetal death in the 13th and 28th weeks of gestation, respectively. She received early plasma exchange at the 23rd week of gestation during this pregnancy and the fetus was delivered uneventfully. The second patient was a 28-year-old woman with progressive thrombocytopenia, anemia and deterioration of renal and liver function postpartum. She received early plasma exchange and it markedly improved her thrombocytopenia without sequelae. In conclusion, early diagnosis and early initiation of plasmapheresis may improve both maternal and fetal prognosis in thrombotic microangiopathy.
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PMID:Treatment of thrombotic microangiopathy in pregnancy with plasma exchange: a report of two cases. 1263 20

Acute thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder that has previously been described associated with various types of surgery. An association between total abdominal hysterectomy (TAH) and TTP has never been reported. Thrombotic thrombocytopenic purpura is classically characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, azotemia and neurological manifestations. Atypical manifestations of TTP include hepatitis, pancreatitis, acute respiratory distress syndrome, non-occlusive mesenteric ischemia and peripheral digital ischemia. This case report describes the occurrence of acute TTP following TAH and bilateral salpingo-oopherectomy, which manifested with typical and atypical features (i.e. hepatitis, pancreatitis). Plasma exchange therapy resulted in the complete resolution of the process.
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PMID:A case report of total abdominal hysterectomy resulting in acute thrombotic thrombocytopenic purpura with pancreatitis and hepatitis: complete resolution with plasma exchange therapy. 1292 16

Thrombotic thrombocytopenic purpura (TTP) is a severe, occlusive, microvascular "thrombotic microangiopathy" characterized by systemic platelet aggregation, organ ischemia, profound thrombocytopenia, and erythrocyte fragmentation. Failure to degrade "unusually large" (UL) von Willebrand factor (VWF) multimers as they are secreted from endothelial cells probably causes most cases of familial TTP, acquired idiopathic TTP, thienopyridine-related TTP, and pregnancy-associated TTP. The emphasis in this review is the pathophysiology of familial and acquired idiopathic TTP. In each of these entities, there is a severe defect in the function of a plasma enzyme, VWF-cleaving metalloprotease (ADAMTS-13), that normally cleaves hyper-reactive ULVWF multimers into smaller and less adhesive VWF forms. In familial TTP, mutations in the ADAMTS13 gene cause absent or severely reduced plasma VWF-cleaving metalloprotease activity. Acquired idiopathic TTP, in contrast, is the result in many patients of the production of autoantibodies that inhibit the function of ADAMTS-13. Established, evolving, and some of the unresolved issues in TTP pathophysiology will be summarized.
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PMID:von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura. 1472 54

Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia and thrombocytopenia, accompanied by microvascular thrombosis that causes variable degrees of tissue ischemia and infarction. Intravascular coagulation is not a prominent feature of the disorder. Plasma exchange can induce remissions in approximately 80% of patients with idiopathic TTP, but patients have a much worse prognosis when thrombotic microangiopathy is associated with cancer, certain drugs, infections, or tissue transplantation. Recently, acquired autoimmune deficiency of a plasma metalloprotease named ADAMTS13 was shown to cause many cases of idiopathic TTP. This review describes our current understanding of how to use this knowledge clinically. In Section I, Dr. Joel Moake describes the presentation of thrombotic microangiopathy, emphasizing the pathophysiology of idiopathic TTP. Platelets adhere to ultra-large (or "unusually large") von Willebrand factor (ULVWF) multimers that are immobilized in exposed subendothelial connective tissue and secreted into the circulation in long "strings" from stimulated endothelial cells. ADAMTS13 cleaves ULVWF multimers within growing platelet aggregates under flowing conditions, and this normally limits platelet thrombus formation. If ADAMTS13 is absent, either congenitally or due to acquired autoantibodies, platelet-rich microvascular thrombosis proceeds unchecked and TTP ensues. Plasma exchange is effective therapy for idiopathic TTP, probably because it replenishes the deficient ADAMTS13 and removes some of the pathogenic autoantibodies and endothelial-stimulating cytokines. Some patients have a type of thrombotic microangiopathy after transplantation/chemotherapy but do not have severe ADAMTS13 deficiency. The pathogenesis of their disease must differ but remains poorly understood. In Section II, Dr. Toshiyuki Miyata describes recent advances in assay methods that should facilitate routine laboratory testing of ADAMTS13 for patients with thrombotic microangiopathy. ADAMTS13 cleaves a single Tyr-Met bond in domain A2 of the VWF subunit. ADAMTS13 assays based on the cleavage of plasma VWF multimers have been used extensively but require considerable time and expertise to perform. A recombinant substrate containing 73 amino acid residues of VWF domain A2 has been devised that allows short incubation times and rapid product detection by gel electrophoresis or immunoassay. These results should encourage the development of even simpler assays that can be performed in most clinical laboratories. In Section III, Dr. James George provides an update on the long-term prospective study of thrombotic microangiopathy in the Oklahoma TTP-HUS Registry. At presentation, the clinical distinction between idiopathic TTP, various forms of secondary thrombotic microangiopathy, and even Shiga toxin-associated hemolytic uremic syndrome (HUS) can be problematic because the symptoms and laboratory findings often overlap. Consequently, plasma exchange usually is administered to any patient with thrombotic microangiopathy if there is doubt about the cause. The role of ADAMTS13 testing in choosing therapy remains uncertain, but the results do appear to have prognostic significance. Severe ADAMTS13 deficiency is specific for idiopathic TTP and identifies a subgroup with a high likelihood of response to plasma exchange, and high-titer ADAMTS13 inhibitors correlate strongly with a high risk of relapsing disease. Patients with normal ADAMTS13 activity have a much worse prognosis, although many factors probably contribute to this difference. Longitudinal study of these patients will continue to clarify the relationship of ADAMTS13 deficiency to the clinical course of thrombotic microangiopathy.
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PMID:Recent advances in thrombotic thrombocytopenic purpura. 1556 95

To study the dynamic changes of CT perfusion parameters during the first 12 h in the embolic cerebral ischemia models. Local cerebral ischemia model were established in 7 New Zealand white rabbits. All CT scans were performed with a GE Lightspeed 16 multislice CT. Following the baseline scan, further CT perfusion scans were performed at the same locations 20 min, 1-6 h and 8, 10 and 12 h after the embolus delivery. Maps of all parameters were obtained by CT perfusion software at each time point. The brains, taken 12 h after the scan, were sliced corresponding to the positions of the CT slices and stained by 2,3,5-triphenyltetrazolium chloride (TTC). On the basis of the TTC results, the ischemic sides were divided into 3 regions: core, penumbra and the relatively normal region. The changes of all parameters were then divided into 3 stages. In the first two hours (the first stage), the CBV dropped more remarkably in the core than in the penumbra but rose slightly in the relatively normal region while the CBF decreased and MTT, TTP extended in all regions to varying degrees. In the 2nd-5th h (the second stage), all the parameters fluctuated slightly around a certain level. In the 5th-12th h (the third stage), the CBV and CBF dropped, and MTT and TTP were prolonged or shortened slightly in the core and penumbra though much notably in the former while the CBV, CBF rose and MTT, TTP were shortened remarkably in the relatively normal region. We experimentally demonstrated that the location and extent of cerebral ischemia could be accurately assessed by CT perfusion imaging. The pathophysiology of the ischemia could be reflected by the CT perfusion to varying degrees.
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PMID:Dynamic changes of the CT perfusion parameters in the embolic model of cerebral ischemia. 1579 58

The thrombotic thrombocytopenic-hemolytic uremic (TTP-HUS) syndrome is a thrombotic microangiopathy involving end-organ vascular beds. Microcirculatory thrombosis results in ischemic changes in any number of organ systems, especially the central nervous and renal systems. Musculoskeletal system involvement is less well described, but when it occurs, acral ischemia may be severe. TTP-HUS is well recognized as a complication of organ transplantation, drug therapy, in pregnancy, and as a chronic, relapsing congenital disorder. Bacterial sepsis may also result in a thrombotic microangiopathy of the central nervous and renal systems (TTP-HUS). This article presents a case report and discusses the pathogenesis and lower-extremity manifestations of TTP-HUS, and outlines management strategies.
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PMID:Foot manifestations of the thrombotic thrombocytopenic purpura hemolytic-uremic syndrome: a review and case report. 1601 39


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