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Common Clotting Pathway

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841. Posaconazole (NoxafilR)

fungal infections, cases of liver failure and death were reported though drug attribution could not be detem~ined. In con~parative studies, elevation of transaminases was seen in all the azoles arms, and was somewhat more common in posaconazole-treated patients (91605) than fluconazole- treated (21539) or itraconazole-treated (0158) patients. Cyclosporine dn~g interaction A drug interaction between posaconazole and cyclosporine resulting in elevated cyclosporine levels was reported (...) ) and is a substrate for p- glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. It is also an inhibitor primarily of CYP3A4, therefore information on various drug interactions is summarized in the labeling. An analysis of exposure-response was conducted that showed an association between lower posaconazole levels and lower clinical efficacy in study 3 16. The recommendation was that the following information be included

2006 FDA - Drug Approval Package

842. Ceprotin - human protein C

. Thrombin rapidly activates PC after binding to thrombomodulin, a membrane receptor protein found on endothelial cells. The PC pathway provides a natural mechanism to control the coagulation system and to prevent excessive clotting. In individuals with a deficiency of PC the defect in the control mechanism leads to increased coagulation activation, resulting in thrombin generation and ultimately intravascular clot formation with thrombosis. An inherited PC deficiency is autosomal in nature (...) aspects The anticoagulant activity of activated protein C is easily demonstrated in in vitro clotting assays in which the addition of activated protein C [APC] to plasma produces a dose-dependent prolongation of clotting time. This is well demonstrated in the literature and probably reported best by Okajima et al. (1990), which showed a dose-dependent effect on the APTT of human plasma in the presence of a purified human protein C concentrate activated by snake venom as well as a purified thrombin

2005 European Medicines Agency - EPARs

843. Angiox (bivalirudin)

to inhibit clot-bound thrombin and consequently the secondary and primary mediated pathways for thrombin activation. Safety pharmacology The only effects of any consequence observed in the safety pharmacology screening studies were on the cardiovascular system in rats and dogs; bivalirudin, 1 or 5 mg·kg -1 iv caused a dose- related increase (~30% at the higher dose) in both systolic and diastolic blood pressure in the rat. A dose of 5 mg·kg -1 , given as an iv infusion over 15 minutes increased blood (...) angioplasty (PTCA) procedures like angioplasty and balloon angioplasty and PTCA with stenting. Patients with ischaemic heart disease are treated with medical therapy, PCI and CABG. The number of PCI performed in Europe now exceeds 500,000 per year. The technique involves positioning of a balloon within the coronary artery, which is then inflated to distend the occlusion. The ensuing damage to the arterial wall releases tissue factor, causes platelet adhesion and aggregation and starts the clotting cascade

2005 European Medicines Agency - EPARs

844. Arixtra (fondaparinux sodium)

. This probably contributes to the minor inhibitory effects of fondaparinux on factor IXa and on factor X activation observed. Fondaparinux does not alter prothrombin time and only slightly prolongs aPTT (maximal mean prolongation 20%) after 0.35-30 mg s.c., and 2-20 mg i.v. The aPTT was doubled only at plasma concentrations above 73 mg/l, whereas it is doubled at 2.5 mg/l UFH. Activated clotting time (ACT) has been measured only in patients undergoing PTCA after fondaparinux 12 mg IV. Inconsistent ACT (...) was approximately 8.2 ± 1.1l after s.c injections of 2.5mg. Fondaparinux is highly bound to ATIII (97.0-98.6%) and in vitro studies have shown that the binding becomes saturated at concentrations above 2 mg/l. The fondaparinux concentration-time profile is described by a bi-exponential decline. The terminal half-life estimates varied between 13 and 21h and the CL/F ranged from 5.1 – 7.9 ml/min, with renal excretion being the major elimination pathway. The renal CL exceeds the filtration CL and, thus

2005 European Medicines Agency - EPARs

845. BeneFIX (nonacog alfa(

BeneFIX (nonacog alfa( 1/11 ?EMEA 2005 SCIENTIFIC DISCUSSION This module reflects the initial scientific discussion for the approval of BeneFIX. This scientific discussion has been updated until 1 September 2000. For scientific information on procedures after this date please refer to module 8B. 1. Introduction Haemophilia B is an inherited bleeding disorder characterised by the deficiency in clotting factor IX (FIX), 4 to 8 times less common than haemophilia A. There are less than 10,000 (...) patients with haemophilia B in the US and Europe. The frequency and type of haemorrhages in individuals with haemophilia B depend on the age of the individual and severity of the defect in haemostatic function. Factor IX plays an essential role in both the extrinsic and intrinsic haemostatic pathway. Individuals with “severe” haemophilia B have FIX levels = 1 International Units (IU) per dl. Persons with “moderate” haemophilia B have FIX activity levels of 1 to 5 IU/dl and individuals with “mild

2005 European Medicines Agency - EPARs

846. Bendamustine (Treanda)

, and Interaction Workup 88 7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class 88 7.3 Major Safety Results and Discussion 89 7.3.1 Deaths 89 7.3.2 Nonfatal Serious Adverse Events 94 7.3.3 Dropouts and/or Discontinuations 96 7.3.5 Submission Specific Primary Safety Concerns 97 7.4 Safety Results and Discussion 98 7.4.1 Common Adverse Reactions 98 7.4.2 Laboratory Findings 100 7.4.3 Vital Signs 106 7.4.4 Electrocardiograms (ECGs) 107 7.4.5 Special Safety Studies 108 7.4.6 Immunogenicity (...) myelosuppression which can lead to life-threatening infections, bleeding, and complications of anemia. Gastrointestinal toxicity consisting of nausea, vomiting, stomatitis, and diarrhea is common with alkylating agents. Alkylating agents are considered carcinogenic, which can lead to secondary malignancies which are typically resistant to available therapies. Alkylating agents are likely to be mutagenic and teratogenic in humans. Alkylating agents can produce human infertility. Intravenous alkylating agents

2007 FDA - Drug Approval Package

847. aPTT

that coagulation tests such as the PT and PTT are based on what happens artificially in the test setting ( in vitro ) and thus do not necessarily reflect what actually happens in the body ( in vivo ). Nevertheless, they can be used to evaluate certain components of the hemostasis system. The PTT and PT tests each evaluate coagulation factors that are part of different groups of chemical reaction pathways in the cascade, called the intrinsic, extrinsic, and common pathways. (For more on this, see the article (...) on the .) How is the sample collected for testing? A blood sample is obtained by inserting a needle into a vein in the arm. Is any test preparation needed to ensure the quality of the sample? No test preparation is needed; however, a high-fat meal prior to the blood draw may interfere with the test and should be avoided. Accordion Title Common Questions The PTT is used primarily to investigate unexplained bleeding or clotting. It may be ordered along with a to evaluate , the process that the body uses

2004 Lab Tests Online USA

848. PT

little can lead to excessive bleeding; too much may lead to excessive clotting. In a test tube during a laboratory test, there are two "pathways" that can initiate clotting, the so-called extrinsic and intrinsic pathways. Both of these then merge into a common pathway to complete the clotting process. The PT test evaluates how well all of the coagulation factors in the extrinsic and common pathways of the coagulation cascade work together. Included are: factors I (Fibrinogen), II (Prothrombin), V (...) , VII and X. The PT/INR may be done at the same time as a PTT, which evaluates the clotting factors that are part of the intrinsic and common pathways: XII, XI, IX, VIII, X, V, II (prothrombin), and I (fibrinogen) as well as prekallikrein (PK) and high molecular weight kininogen (HK). The PT and PTT evaluate the overall ability to produce a clot in a reasonable amount of time and, if any of these factors are deficient in quantity or not functioning properly, the test results will be prolonged

2004 Lab Tests Online USA

849. Citrate Effects and Bone Density in Long-Term Apheresis Donors

in the U.S., including 3,500 in the Platelet Center of the Department of Transfusion Medicine, NIH. Healthy donors are eligible to undergo plateletpheresis as often as 24 times per year. During plateletpheresis, citrate anticoagulant is added to the blood collection pathway to prevent clotting in the apheresis device, and is infused into the donor during the procedure.1-3 Adverse effects related to citrate administration are common; the most well-studied is acute hypocalcemia due to the formation (...) by spinning. The desired cells are removed and the rest of the blood is returned to the donor, either through the same needle or through a needle in the other arm. A blood thinning medicine called citrate is added to the cell-separating machine. Citrate reduces the ionized calcium levels in the blood, which prevents the blood from clotting. When the blood is returned to the donor, the donor also receives the citrate. This lowers the donor's ionized calcium levels which may irritate nerve and muscle cells

2003 Clinical Trials

850. Molecular and Cellular Characterization of Spongiotic Dermatitis

pathways involved in these diseases and development of novel therapeutic agents. Condition or disease Atopic Dermatitis Psoriasis Contact Dermatitis Detailed Description: Spongiotic dermatitis is the histopathologic diagnosis commonly issued by dermatopathologists that encompasses atopic dermatitis, contact dermatitis, and other forms of eczematous dermatitis. Atopic dermatitis is a chronic, relapsing inflammatory disease characterized by pruritic, scaly, red, eczematous skin lesions, and a personal (...) , and psoriasis by microarray analyses. Confirmation of protein expression profiles in atopic and contact dermatitis, and psoriasis by immunohistochemical analyses. Identification of disease-specific potential diagnostic markers in plasma and PBMC. The information obtained will assist in development of diagnostic methods for differentiation of the types of spongiotic dermatitis. This study also has the potential to lead to the dissection of pathologic pathways involved in these diseases and development

2006 Clinical Trials

851. Frailty and risk of venous thromboembolism in older adults. (PubMed)

Frailty and risk of venous thromboembolism in older adults. Frailty is a common risk factor for morbidity and mortality in elderly persons. Recent evidence links frailty to activation of coagulation and inflammatory pathways. We aimed to determine whether frailty in community-dwelling older adults is a risk factor for venous thromboembolism (VTE).We conducted a prospective cohort study in four U.S. communities involving 4859 participants 65 years old and older. At baseline, in 1989-1993, we (...) interval [CI], 0.93-1.84). The comparably adjusted relative risk for idiopathic VTE (n = 58) was 1.79 (95% CI, 1.02-3.13).The incidence rates of idiopathic VTE was higher in community-dwelling older adults with baseline frailty compared with no frailty. Further studies of the clotting process in frailty may allow the development of an improved strategy to determine VTE risk in this vulnerable subset of older adults.

2007 Biological Sciences and Medical Sciences

852. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management. (PubMed)

Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management. Normal coagulation has classically been conceptualized as a Y-shaped pathway, with distinct "intrinsic" and "extrinsic" components initiated by factor XII or factor VIIa/tissue factor, respectively, and converging in a "common" pathway at the level of the FXa/FVa (prothrombinase) complex. Until recently, the lack of an established alternative concept of hemostasis has meant (...) that most physicians view the "cascade" as a model of physiology. This view has been reinforced by the fact that screening coagulation tests (APTT, prothrombin time--INR) are often used as though they are generally predictive of clinical bleeding. The shortcomings of this older model of normal coagulation are nowhere more apparent than in its clinical application to the complex coagulation disorders of acute and chronic liver disease. In this condition, the clotting cascade is heavily influenced

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2006 Hepatology

853. Thrombokinetic Studies in Normal and Factor VIII-deficient Canine Plasmas (PubMed)

Thrombokinetic Studies in Normal and Factor VIII-deficient Canine Plasmas Thrombokinetograms are graphic depictions of the optical changes occurring in plasma during the clotting process and provide information, not only on the time required for clotting to begin, but also on the way in which the clot forms. We studied thrombokinetic profiles in plasmas from normal dogs, and dogs with varying degrees of factor VIII deficiency. Clotting was induced through intrinsic, extrinsic and common (...) coagulation pathways [activated partial thromboplastin time, prothrombin time and thrombin time, respectively]. The thrombokinetograms for the various clotting tests were qualitatively similar in normal canine plasmas. After activation of the clotting system there was a period in which no change in optical density occurred. This period was represented by the left base line and corresponded to the duration of the clotting time. When fibrin production commenced there was a rapid increase in the rate

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1983 Canadian Journal of Comparative Medicine

854. Activated human protein C prevents thrombin-induced thromboembolism in mice. Evidence that activated protein c reduces intravascular fibrin accumulation through the inhibition of additional thrombin generation. (PubMed)

occlusion rate (from 89.2 to 46.6%, P < 0.01). The protective effect of APC was due to the inhibition of endogenous thrombin formation as indicated by the fact that (a) the injection of human thrombin caused a marked decrease in the coagulation factors of the intrinsic and common pathways (but not of Factor VII), suggesting the activation of blood clotting via the contact system; (b) APC pretreatment reduced markedly prothrombin consumption; (c) the lethal effect of thrombin was almost abolished when (...) speculate that the inhibition of additional (endogenous) thrombin formation by APC interrupts thrombin-dependent mechanisms that make fibrin clots more resistant to lysis, so that the intravascular deposited fibrin can be removed more rapidly by the endogenous fibrinolytic system.

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1998 Journal of Clinical Investigation

855. Role of endotoxemia in cardiovascular dysfunction and mortality. Escherichia coli and Staphylococcus aureus challenges in a canine model of human septic shock. (PubMed)

abnormalities of septic shock as E. coli. These findings indicate that structurally and functionally distinct microorganisms, with or without endotoxin, can activate a common pathway resulting in similar cardiovascular injury and mortality. (...) Role of endotoxemia in cardiovascular dysfunction and mortality. Escherichia coli and Staphylococcus aureus challenges in a canine model of human septic shock. Using different types of bacteria and a canine model simulating human septic shock, we investigated the role of endotoxin in cardiovascular dysfunction and mortality. Either Escherichia coli (a microorganism with endotoxin) or Staphylococcus aureus (a microorganism without endotoxin) were placed in an intraperitoneal clot in doses

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1989 Journal of Clinical Investigation

856. On the role of phosphatidylethanolamine in the inhibition of activated protein C activity by antiphospholipid antibodies. (PubMed)

dependent. In three patient plasmas, these phenomena are shown to be due to immunoglobulins. The PE requirement in the expression of activated protein C anticoagulant activity and the PE dependence of some antiphospholipid antibodies provide a mechanistic basis for the selective inhibition of the protein C pathway. Inhibition of activated protein C function may be a common mechanism contributing to increased thrombotic risk in certain patients with antiphospholipid antibodies. (...) On the role of phosphatidylethanolamine in the inhibition of activated protein C activity by antiphospholipid antibodies. Phosphatidylethanolamine (PE) is an important membrane component for supporting activated protein C anticoagulant activity but has little influence on prothrombin activation. This difference constitutes a potential mechanism for selective inhibition of the protein C anticoagulant pathway by lupus anticoagulants and/or antiphospholipid antibodies. In this study, we

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1995 Journal of Clinical Investigation

857. The impact of tissue factor pathway inhibitor on coagulation kinetics determined by thrombelastography. (PubMed)

values. Thrombelastography (TEG) is often used to monitor hemostasis in the perioperative period, and TFPI could potentially affect the diagnostic interpretation of TEG-based data, given its inhibition of both common and TF coagulation pathways. Thus, in this study we characterized the effect of TFPI on coagulation kinetics via TEG.Whole blood, Factor VII-deficient plasma, and normal plasma were exposed in vitro to various concentrations of TFPI, after which unmodified, celite-activated, and TF (...) The impact of tissue factor pathway inhibitor on coagulation kinetics determined by thrombelastography. Tissue factor pathway inhibitor (TFPI) is a 40-kDa, endogenous protein that inhibits tissue factor (TF)-initiated coagulation by bonding with activated factor X (FXa). The TFPI/FXa complex then subsequently binds with TF/activated factor VII (FVIIa) complex, ultimately inhibiting thrombin generation. Heparin administration causes endothelial release of TFPI concentrations up to sixfold normal

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2006 Anesthesia and Analgesia

858. Clotting Genetic Variants, Hormones, and Venous Thrombosis

will be reviewed to determine study eligibility and to collect V'i'E risk factor information. Hormone and SERM use will be ascertained from the GHC pharmacy database. Phlebotomy will be performed on surviving cases and controls to collect plasma samples and genetic information. Logistic regression analyses will determine which haplotypes of key elements in the clotting pathways modify the association between hormones or SERMSs and VTE risk. The identification of common genetic variants that either increase (...) ), and selective estrogen receptor modulators (SERMs). Epidemiologic data suggest that genetic variation in the pro-coagulant, anti-coagulant, and fibrinolytic pathways may modify the risk of VTE in women, especially in the presence of hormone use. The primary aim of this study is to identify genetic variants in 12 key clotting proteins that may modify the risk of VTE independently, through gene-gene interactions, and in the presence of HRT, OC, or SERM use. Proteins include thrombomodulin, protein C

2004 Clinical Trials

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