Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hematologic disorders are frequently encountered in the intensive care unit. Thrombocytopenia, often defined as a platelet count below 100,000/microL, is common in critically ill patients and may be associated with adverse outcomes. A systematic evaluation of clinical and laboratory findings is necessary to ascertain the cause of the thrombocytopenia and to determine the correct therapy. Recognition of heparin-induced thrombocytopenia (HIT) is particularly important, given the risk of thrombosis associated with this condition. Prompt cessation of all heparin products is required, and anticoagulation with a direct thrombin inhibitor is recommended if HIT is strongly suspected. Coagulopathies are also common in the critically ill, and are often due to vitamin K deficiency or disseminated intravascular coagulation (DIC). A careful history and interpretation of clotting studies are useful in defining the coagulation defect. Advances in understanding the pathogenesis of DIC have generated new treatment approaches, such as the use of recombinant activated protein C. Recombinant factor VIIa (rFVIIa) is a novel drug approved for use in patients with congenital hemophilia and inhibitors. Although its use as a hemostatic agent is currently being evaluated in several off-label scenarios, including trauma, intracerebral hemorrhage, and liver disease, there are limited data to guide therapy in these conditions.
 ...
PMID:Hematologic disorders in critically ill patients. 1679 61

The peculiar pathogenesis of heparin-induced thrombocytopenia (HIT), involving a "self" antigen-platelet factor 4 (PF4) bound to heparin-and resulting antibody-mediated platelet activation, is a model for thrombosis triggered by drug-induced autoimmunity. The high probability of forming an immune response to heparin, and the highly-variable clinical significance of a positive laboratory test-depending on the type of assay and the magnitude of a given positive test result-provides lessons regarding appropriate interpretation of diagnostic laboratory testing in the context of pretest probability. The relatively high risk of inducing microvascular thrombosis due to coumarin-induced vitamin K antagonism attests to the dangers of a compromised protein C natural anticoagulant system in the setting of a hypercoagulability state such as HIT. Unusual immunologic features of HIT, such as the dissociation between immunogenicity (induction of immune response) and cross-reactivity (capacity to form the antigens recognized by HIT antibodies)of the implicated polysaccharide anticoagulants, and the generally rapid formation and disappearance of anti-PF4/heparin antibodies, suggest that further lessons regarding HIT immunopathogenesis remain to be learned.
 ...
PMID:HIT: lessons learned. 1685 47

Skin necrosis caused by heparins is a rare complication. We report a case of a 71-yr-old white woman who developed painful diffuse skin lesions, most probably related to enoxaparin treatment. Other causes of skin necrosis, including heparin induced thrombocytopenia, disseminated intravascular coagulation, protein C/protein S deficiencies, anti-phospholipid antibodies, and vitamin K deficiency were less likely in this case. The concomitant combined thrombophilia possibly aggravated the patient's clinical presentation.
 ...
PMID:A fatal case of enoxaparin induced skin necrosis and thrombophilia. 1685 10

Coagulation factor defects, thrombocytopenia, and thrombocytopathy are associated with cirrhosis. However, bleeding in patients who have cirrhosis does not entirely correlate with abnormal coagulation tests. Recently, it was shown that because of the concomitant abnormalities of the procoagulant and anticoagulant drives, thrombin generation in plasma patients with cirrhosis is normal when assessed with assays that include thrombomodulin (the main protein C activator). However, thrombin is also generated in vivo as a function of platelets, suggesting that thrombocytopenia and thrombocytopathy might affect thrombin generation in patients with cirrhosis. We addressed this issue using an assay that accounts for the contribution of plasma and platelets. The study showed that platelet-rich plasma with platelets adjusted by dilution of autologous platelet-rich into autologous platelet-poor plasma to a standard count (100 x 10(9)/L) generates as much thrombin in patients with cirrhosis as in controls (1,063 nmol/L vs. 1,167 nmol/L; P value not significant). When platelets were adjusted to correspond to whole-blood counts, patients with cirrhosis generated significantly less thrombin than controls (949 nmol/L vs. 1,239 nmol/L; P < .001). Furthermore, thrombin generation correlated with platelet numbers (rho = 0.50; P < .001). In addition, the amount of thrombin generated as a function of the whole-blood patients' platelet counts increased significantly when the numbers were adjusted to 100 x 10(9)/L (953 nmol/L vs.1,063 nmol/L; P < .001). In conclusion, severe thrombocytopenia may limit thrombin generation in patients with cirrhosis. These findings might justify platelet transfusion in patients with low platelet counts when they bleed spontaneously or before undergoing surgery or liver biopsy. Controlled clinical trials supporting this indication are warranted.
 ...
PMID:Thrombin generation in patients with cirrhosis: the role of platelets. 1687 42

The anticoagulant, activated protein C (aPC), possesses antithrombotic, profibrinolytic, anti-inflammatory, and antiapoptotic properties, and the level of this protein is an important marker of acute inflammatory responses. Although infusion of aPC improves survival in a subset of patients with severe sepsis, evidence as to how aPC decreases mortality in these cases is limited. Because a total deficiency of PC shows complete neonatal lethality, no animal model currently exists to address the mechanistic relationships between very low endogenous aPC levels and inflammatory diseases. Here, we show for the first time that novel genetic dosing of PC strongly correlates with survival outcomes following endotoxin (LPS) challenge in mice. The data provide evidence that very low endogenous levels of PC predispose mice to early-onset disseminated intravascular coagulation, thrombocytopenia, hypotension, organ damage, and reduced survival after LPS challenge. Furthermore, evidence of an exacerbated inflammatory response is observed in very low PC mice but is greatly reduced in wild-type cohorts. Reconstitution of low-PC mice with recombinant human aPC improves hypotension and extends survival after LPS challenge. This study directly links host endogenous levels of PC with various coagulation, inflammation, and hemodynamic end points following a severe acute inflammatory challenge.
 ...
PMID:Acute inflammation is exacerbated in mice genetically predisposed to a severe protein C deficiency. 1704 51

New onset thrombocytopenia and multiple organ failure (TAMOF) presages poor outcome in critical illness. Patients who resolve thrombocytopenia by day 14 are more likely to survive than those who do not. Patients with TAMOF have a spectrum of microangiopathic disorders that includes thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC) and secondary thrombotic microanigiopathy (TMA). Activated protein C is effective in resolving fibrin-mediated thrombosis (DIC); however, daily plasma exchange is the therapy of choice for removing ADAMTS 13 inhibitors and replenishing ADAMTS 13 activity which in turn resolves platelet: von Willebrand Factor mediated thrombosis (TTP/secondary TMA).
 ...
PMID:Bench-to-bedside review: thrombocytopenia-associated multiple organ failure--a newly appreciated syndrome in the critically ill. 1709 64

Heparin-induced thrombocytopenia, or HIT, can present in many ways, ranging from common-isolated thrombocytopenia, venous thromboembolism, acute limb ischemia-to less common but specific presentations-necrotizing skin lesions at heparin injection sites, post-bolus acute systemic reactions, and adrenal hemorrhagic necrosis (secondary to adrenal vein thrombosis). Many patients with HIT have mild or moderate thrombocytopenia: the median platelet count nadir is 60 x 10(9)/L, and ranges from 15 to 150 x 10(9)/L in 90% of patients, most of whom evince a 50% or greater fall in the platelet count. HIT that begins after stopping heparin ("delayed-onset HIT") is increasingly recognized. Factors influencing risk of HIT include type of heparin (unfractionated heparin > low-molecular-weight heparin), type of patient (surgical > medical), and gender (female > male). Since timely diagnosis and treatment of HIT may reduce the risk of adverse outcomes, this review focuses on those clinical circumstances that should prompt the clinician to "think of HIT." Coumarin anticoagulants such as warfarin are ineffective in acute HIT and can even be deleterious by predisposing to micro-thrombosis via protein C depletion (venous limb gangrene and skin necrosis syndromes). Thus, it is important to avoid or postpone coumarin while managing HIT hypercoagulability, focusing on agents that inhibit thrombin directly (lepirudin, argatroban) or that inhibit its generation (danaparoid, fondaparinux). Post-marketing experience suggests that standard dosing of lepirudin is too high; current recommendations are to avoid the initial lepirudin bolus and to begin with lower infusion rates, even in patients without overt renal dysfunction.
 ...
PMID:Think of HIT. 1712 91

Antiphospholipid antibodies (aPL) are a heterogeneous group of autoantibodies, detected in the sera of patients with both autoimmune and various non-autoimmune diseases. They are also detected in subjects with no overt underlying disease - the primary antiphosphilipid syndrome (PAPS). High titers of APL are associated with arterial and venous thrombosis, recurrent fetal loss and thrombocytopenia. There have been many suggestions explaining the potential mechanisms of the procoagulant effect of aPL. These include endothelial cell (EC) activation; increased adhesion molecule expression; inhibition of EC prostacyclin release, increased leucocyte adhesion to EC, downregulation of thrombomodulin expression. APL induce the procoagulant activity of monocytes via increased tissue factor expression and directly stimulate platelet hyperactivity with resultant production of enhanced amounts of the proaggregatory molecule of TXA(2). In vitro studies show that prepro-endothelin-1 mRNA is induced by human monoclonal anticardiolipin antibodies and this might contribute to vasospasm, and, ultimately, to arterial occlusion. The hypercoagulable state in APS patients is associated with alterations in the protein C/S pathway. It is suggested that aPL may impair the protein C anticoagulant system. Acquired protein C and protein S deficiency is described in patients with APS. Beta2- glycoprotein I, (Beta2-GPI) a natural anticoagulant, is involved in the regulation of protein S anticoagulant activity by preventing the binding of protein S to C4b-binding protein. APL were shown to inhibit this effect of Beta2- GP I. As the group of aPL is very heterogeneous, it is unlikely that a single mechanism is responsible for the thrombogenic activity of all aPLs associated with thrombosis.
 ...
PMID:Some recent insights into the prothrombogenic mechanisms of antiphospholipid antibodies. 1734 65

Thrombocytopenia is a common problem in critically ill patients, which is associated with increased mortality. Recently, Drotrecogin alfa (activated) (recombinant human activated protein C (APC)) was shown to reduce mortality in patients with severe sepsis. Only minimal effect of APC on coagulation markers was demonstrated. Nevertheless, low platelet count was identified as a risk factor for bleeding with use of this drug. We conducted this study to evaluate possible influence of APC on in vitro expression of platelet receptors at therapeutic and supra-therapeutic concentrations. Blood samples of volunteers and patients with severe sepsis were adjusted with APC to final concentrations of 0.045 microg mL(-1) APC (APC-45, therapeutic dose) and 0.225 microg mL(-1) APC (APC-225, five-fold therapeutic dose), respectively. The activation of platelets was mediated by two different agonists. APC had no significant influence on platelet activation, with or without stimulation at both concentrations. In group APC-225, CD62P showed a non-significant decrease. This in vitro study demonstrates that therapeutic plasma concentrations of Drotrecogin alfa (activated) have neither influence on expression of platelet activation markers nor on platelet-granulocyte complexes in blood of volunteers and patients with severe sepsis. Thus, a direct drug-platelet interaction seems unlikely.
 ...
PMID:Effect of Drotrecogin alfa (activated) on platelet receptor expression in vitro. 1765 7

Enoxaparin, a low-molecular-weight heparin used to treat and prevent deep venous thrombosis, has been evaluated in several clinical trials. Thrombosis induced by enoxaparin with no evidence of heparin-induced thrombocytopenia (HIT) is seldom described. We report a rare case in which an 89-year-old African-American female developed large, multiple, painful lesions induced by enoxaparin administration. Laboratory investigations for HIT, disseminated intravascular coagulation, protein C, protein S, factor V, factor VIII, antithrombin III, and homocysteine deficiency were negative. Unfortunately, despite aggressive management for 2 weeks, the patient developed severe sepsis and died.
 ...
PMID:Enoxaparin-induced skin necrosis: a fatal outcome. 1766 18


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>