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)

Ischemia is increasingly recognized as a cause of cholangiopathy. The aim of this study was to report a case of association of paroxysmal nocturnal hemoglobinuria with abrupt-onset cholangiopathy. Anomalies resembling sclerosing cholangitis were documented in a patient suffering from recurrent biliary pain. None of the conditions that have been associated with primary sclerosing cholangitis or other forms of cholangiopathy was present, but shortly thereafter, paroxysmal nocturnal hemoglobinuria occurred. Hepatic vein thrombosis later complicated the course of the disease. Because the fortuitous coincidence of these uncommon conditions is unlikely, this case indicates that paroxysmal nocturnal hemoglobinuria is a cause of ischemic cholangiopathy. Other thrombogenic conditions may also be implicated in some instances of apparently idiopathic cholangiopathy.
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PMID:Cholangitis associated with paroxysmal nocturnal hemoglobinuria: another instance of ischemic cholangiopathy? 755 5

Paroxysmal nocturnal hemoglobinuria is an acquired clonal expansion of bone marrow stem cells that are deficient in the decay-accelerating factor, which is a complement regulatory glycoprotein (CD55), as well as in the membrane inhibitor of reactive lysis (CD59) and the C8-binding protein. These proteins are deficient on the membranes of red blood cells, granulocytes, monocytes, and platelets. The disorder is associated with intermittent hemolytic anemia, hemoglobinuria, infection, a tendency toward bone marrow aplasia, and venous thromboses. The thromboses, on resolution, may give rise to endothelial proliferation that may cause ischemia and ulceration, or, alternatively, the thromboses may cause ulceration leading to a granulation tissue response with exaggerated endothelial proliferation. We report a second case of paroxysmal nocturnal hemoglobinuria that presented roentgenographically as an ulcerated circumferential duodenal mass secondary to venous thrombosis accompanied by florid papillary endothelial hyperplasia. We also review the literature concerning this phenomenon.
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PMID:Paroxysmal nocturnal hemoglobinuria associated with venous thrombosis and papillary endothelial hyperplasia presenting as ulcerated duodenal mass. 806 Feb 37

Thrombotic complications, particularly microthrombi involving intraabdominal veins leading to intestinal ischemia, have remained a major cause of morbidity in patients with paroxysmal nocturnal hemoglobinuria (PNH). While intestinal ischemia has been postulated to be the cause of recurrent bouts of abdominal pain in this population, direct antemortem evidence for this complication is scarcely documented in the literature. We describe a case of PNH in a patient who presented with abdominal distress three years after the initial diagnosis was established. Clinical features and a combination of diagnostic modalities, including radiography, endoscopy, and histology were used to make the prompt diagnosis of intestinal ischemia. This is the first case in which the electronic microscopy of the gastrointestinal lesion is described. Our patient was successfully treated with conservative measures and anticoagulation.
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PMID:Gastrointestinal involvement in paroxysmal nocturnal hemoglobinuria: first report of electron microscopic findings. 1183 33

Paroxysmal nocturnal hemoglobinuria is rarely associated with intestinal complications. We report a case of paroxysmal nocturnal hemoglobinuria with small bowel ischemia leading to ileal perforation. In the literature, an ulcerative jejuno-ileitis has been reported in 6 cases of intestinal ischemia, due to thrombosis of mucosal small vessels. This disease is usually revealed by abdominal pain. Based on published cases and our observation of intestinal ischemia leading to small bowel perforation, surgery should be considered as the first-line treatment, especially when small bowel lesions are limited.
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PMID:[Paroxysmal nocturnal hemoglobinuria associated with intestinal ischemia leading to small bowel perforation]. 1463 8

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disorder characterized by hemolytic anemia, hemoglobinuria, bone marrow failure, and hypercoagulability. Thrombosis is the leading cause of mortality and occurs in one-half of PNH patients, with the hepatic veins being the most common site. Patients with hepatic vein thrombosis (Budd-Chiari syndrome) can present with abdominal pain, hepatomegaly, jaundice, and ascites. Prognosis is poor for these patients; death may occur from liver failure, vessel rupture, intestinal ischemia, infarction, necrosis, or sepsis. The authors report three consecutive cases of successful treatment with catheter-directed thrombolysis and thrombectomy directly in the hepatic veins in patients with PNH who developed acute hepatic vein thrombosis. This treatment represents a potential bridge toward more curative therapies such as allogeneic bone marrow transplant.
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PMID:Catheter-directed thrombolysis and thrombectomy for the Budd-Chiari syndrome in paroxysmal nocturnal hemoglobinuria in three patients. 1651 88

Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described.
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PMID:Biphenylsulfonyl-thiophene-carboxamidine inhibitors of the complement component C1s. 1824 91

The complement system, an essential part of the innate immune system, defends the host against invading pathogens, prevents immune complex disease and aids the acquired immune response. Under normal conditions the host is protected from complement attack by an array of complement regulatory proteins. However, in certain contexts inappropriate complement activation can occur associating the C system with a variety of disease pathologies. This review focuses upon the role complement plays in a number of renal pathologies as well as the role of complement in three examples of extrarenal diseases: paroxysmal nocturnal hemoglobinuria, age-related macular degeneration and liver fibrosis. From the evidence discussed it is clear that mutations or polymorphisms in the complement regulators resulting in reduced levels or inefficient action dramatically enhance susceptibility to certain diseases and in particular render the kidney more vulnerable to complement attack. Additionally, deficiency in the complement components can predispose to disease through reduced clearance of apoptotic cells and subsequent generation of complement activating autoantibodies or enhanced formation of convertases resulting in heightened complement activation. As complement has devastating effects, in such disease contexts it has become a therapeutic target. Therapeutic intervention strategies discussed here focus upon the use of recombinant agents, the most promising of which are the anti-C5 antibody-derived reagents. These agents have proved effective in the treatment of paroxysmal nocturnal hemoglobinuria, nephritis and ischemia-reperfusion injuries and will no doubt, along with other reagents currently being developed, prove invaluable in the treatment of renal pathologies.
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PMID:Complement, roles in renal disease and modulation for therapy. 1900 May 36

Activation of the complement system is a major pathogenic event that drives various inflammatory responses in numerous diseases. All pathways of complement activation lead to cleavage of the C5 molecule generating the anaphylatoxin C5a and, C5b that subsequently forms the terminal complement complex (C5b-9). C5a exerts a predominant pro-inflammatory activity through interactions with the classical G-protein coupled receptor C5aR (CD88) as well as with the non-G protein coupled receptor C5L2 (GPR77), expressed on various immune and non-immune cells. C5b-9 causes cytolysis through the formation of the membrane attack complex (MAC), and sub-lytic MAC and soluble C5b-9 also possess a multitude of non-cytolytic immune functions. These two complement effectors, C5a and C5b-9, generated from C5 cleavage, are key components of the complement system responsible for propagating and/or initiating pathology in different diseases, including paroxysmal nocturnal hemoglobinuria, rheumatoid arthritis, ischemia-reperfusion injuries and neurodegenerative diseases. Thus, the C5-C5a receptor axis represents an attractive target for drug development. This review provides a comprehensive analysis of different methods of inhibiting the generation of C5a and C5b-9 as well as the signalling cascade of C5a via its receptors. These include the inhibition of C5 cleavage through targeting of C5 convertases or via the C5 molecule itself, as well as blocking the activity of C5a by neutralizing antibodies and pharmacological inhibitors, or by targeting C5a receptors per se. Examples of drugs and naturally occurring compounds used are discussed in relation to disease models and clinical trials. To date, only one such compound has thus far made it to clinical medicine: the anti-C5 antibody eculizumab, for treating paroxysmal nocturnal hemoglobinuria. However, a number of drug candidates are rapidly emerging that are currently in early-phase clinical trials. The C5-C5a axis as a target for drug development is highly promising for the treatment of currently intractable major human diseases.
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PMID:Inhibiting the C5-C5a receptor axis. 2154 29

Antibody-mediated rejection, be it acute, subacute or chronic, is currently recognized as the major cause of graft loss in kidney transplant recipients. Anti-HLA donor-specific antibodies are deleterious to the graft fate whether they pre-exist to the transplantation or appear in the course of transplantation. The role of complement is therefore prominent in most instances. As well, the role of complement activation is crucial in the recurrence of atypical hemolytic uremic syndrome post-transplantation (aHUS) as well as following ischemia-reperfusion injury leading to delayed graft function. Eculizumab, a fully humanized monoclonal antibody directed against the C5 component of the complement cascade is efficient in chronically and safely blocking complement activation for example in paroxysmal nocturnal hemoglobinuria. In the setting of kidney transplantation, there is convincing but still limited evidence that eculizumab is efficient in preventing both acute and chronic antibody-mediated rejection in highly sensitized recipients requiring desensitization before getting a living donor kidney transplant. Studies are currently ongoing to determine its efficacy and safety in ABO incompatible transplantation, in the prevention of acute and chronic rejection either with a living or a deceased donor kidney as well as in the prevention of delayed graft function. Similar to its efficacy in aHUS on native kidneys, eculizumab prevents or treats recurrence after kidney transplantation. There is still a lot of research to be performed in order to determine precisely the exact indications and the length of treatment with this very active but also very expensive drug that will undoubtedly revolutionize the current management of patients with donor specific antibodies (DSAs) and at risk of HUS recurrence.
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PMID:Eculizumab in renal transplantation. 2374 93

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, nonmalignant disorder of hematopoietic stem cells characterized by hemolysis, diminished hematopoiesis, and thrombophilia. We describe a 65-year-old woman with known PNH and peripheral arterial disease who presented with critical limb ischemia and a nonhealing left foot ulcer. She underwent surgical bypass of a diffusely diseased left superficial femoral artery with autologous reversed saphenous vein graft. Her postoperative course was complicated by wound sepsis and PNH exacerbation with resultant graft thrombosis requiring an above-knee amputation. This case highlights several key concepts relevant to the management of vascular surgery patients with PNH: (1) their predisposition for arterial and venous thrombosis; (2) hypercoagulability despite standard anticoagulation regimens; (3) the role of eculizumab (a monoclonal antibody that inhibits complement activation used to treat PNH) in reducing thrombotic complications and hemolysis; and (4) complications associated with the immunosuppressive effects of eculizumab. We recommend careful monitoring of hemolysis and immunosuppression, aggressive anticoagulation, frequent graft surveillance, and early consultation with hematology.
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PMID:Paroxysmal nocturnal hemoglobinuria: a red clot syndrome. 2420 Jan 43


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