Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 57 patients with pregnancy-induced or aggravated hypertension, antithrombin III levels correlated inversely with maternal morbidity. Morbidity was determined by the maximal diastolic blood pressure, disturbance of renal and liver function, and thrombocytopenia. Antithrombin III levels and platelet counts correlated inversely with the degree of placental infarction. Proteinuria (grams per 24 hours) was most predictive of fetal outcome, which was considered to be either favorable if a healthy baby could be discharged with its mother or unfavorable in case of perinatal death or a prolonged stay in the neonatal intensive care unit. Plasma antithrombin III and serum glutamic oxaloacetic transaminase levels, in that order, augmented the number of correct predictions. Antithrombin III inhibits blood coagulation by forming irreversible complexes with activated clotting enzymes, notably with factor Xa and thrombin. Evidence is presented which suggests that antithrombin III levels in preeclampsia are depressed as a result of increased consumption in the maternal vascular tree, rather than decreased synthesis or increased urinary loss.
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PMID:Antithrombin III levels in preeclampsia correlate with maternal and fetal morbidity. 671 44

Protamine reversal of unfractionated and low-molecular-weight heparin (LMWH) causes hypotension, bradycardia, pulmonary artery hypertension, and declines in oxygen consumption. Furthermore, protamine incompletely reverses the anti-Xa activity of LMWH. The present study assesses the efficacy and toxicity of three protamine variants having +16 and +18 charges in reversal of LMWH (Logiparin, LHN-1): [+16] P(AK2A2K2)4, [+18] PK(K2A2K2A)3K2AK3, and [+18B] acetyl-PA(K2A2K2A)4K2-amide. The [+18B] compound was made by acetylating and amidating the [+18] to decrease in vivo degradation and to increase the alpha-helix forming propensity. Variants were examined in a canine model (n = 7, each variant) and compared to controls (n = 7, each variant) and compared to controls (n = 7) reversed with standard protamine with a +21 charge. Animals were anesthetized, anticoagulated with LMWH (150 IU factor Xa activity/kg), and reversed with protamine variants (1.5 mg/kg with 100 IU/mg). Blood pressure (BP), heart rate (HR), cardiac output (CO), pulmonary artery pressures, oxygen saturations, and oxygen consumption (VO2) were continuously monitored. Comparisons were undertaken at baseline, after heparin, before variant administration, and for 30 min thereafter. A total toxicity score (TTS) was calculated for each variant, accounting for maximal declines in BP, HR, CO, and VO2 during the first 5 min after reversal. Protamine [+21] was most toxic, TTS -7.6, with the variants being less toxic (P < 0.01, ANOVA): TTS = [+16] -2.8, [+18] -1.3, and [+18B] -4.1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reversal of low-molecular-weight heparin anticoagulation by synthetic protamine analogues. 801 15

In the present study, thromboviscometry was used to analyse the dynamic coagulation of blood in patients with severe systemic hypertension. Fibrinogen levels and whole blood viscosity, corrected for 45% haematocrit, were also monitored. The efficacy of thromboviscometry as an adjunct diagnostic tool, for determination of thrombogenic potential, was compared with that of detection of fibrinogen levels in the blood. Twenty-five cases of severe systemic hypertension (HT) in the 40 to 50-year age group were compared with 50 age and sex-matched normal controls (NC). The changes in whole blood viscosity were monitored with time at a constant shear rate, in a concentric cylinder viscometer, during the clotting process. The total thrombus formation time was significantly less in the HT group when compared with NC (238.9 +/- 38.72 s vs 315.1 +/- 32.93 s, P < 0.0005). The time required for a sudden increase in viscosity during clotting was also significantly lower in the HT group (205.9 +/- 34.37 s vs 272.9 +/- 28.83 s, P < 0.0005) and the overall rate of increase of thrombus viscosity was significantly higher in HT (245.2 +/- 36.44 centiPoise/s vs 183.6 +/- 16.32 centiPoise/s, P < 0.0005). There was, however, no significant change in the fibrinogen levels of the two groups. Thus, thromboviscometry was a more sensitive indicator of the thrombogenic potential of blood in HT than fibrinogen levels. The increased thrombogenic potential of hypertensive blood could be due to acceleration of the initial part of the coagulation process during the activation of factor Xa and the formation of thrombin.
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PMID:Thromboviscometry as a tool for evaluation of thrombotic risk in systemic hypertension. 1072 16

Circulating platelets play a pivotal role in hemostasis. The platelet hemostatic function involves the direct interaction with damaged vessel walls, and circulating coagulation factors, primarily thrombin resulting in platelet activation, aggregation and formation of hemostatic plug. Flow cytometry is a useful technique for the study of platelet activation in circulating blood. Platelet activation markers for ex vivo analysis may include a) activation-dependent epitopes of the membrane glycoprotein (GP) IIb/IIIa (CD41a) receptor, as demonstrated by the binding of activation-specific monoclonal antibodies (MoAbs) PAC1, anti-LIBS1 and anti-RIBS); b) the expression of P-selectin (CD62p), the alpha-granule GP translocated to the platelet surface following release reaction; and c) platelet procoagulant activity, as demonstrated by the binding of i) annexin V protein to the prothrombinase-complex (prothrombin, activated factor X (Xa) and V (Va)) binding sites on the surface of activated platelets, and of ii) MoAbs against activated coagulation factors V and X bound to the surface of activated platelets. Using this method, platelet activation as a marker for in vivo prothrombotic activity can be demonstrated in various clinical conditions including coronary angioplasty, orthostatic challenge in primary depression, sickle cell disease in clinical remission and during pain episode, and in pregnancy-related hypertension with marked increase during preeclampsia. The finding of platelet procoagulant activity is corroborated by increased levels of plasma markers for thrombin generation and fibrinolytic activity.
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PMID:Platelet activation as a marker for in vivo prothrombotic activity: detection by flow cytometry. 1547 Dec 23

Atrial fibrillation (AF) is an epidemic, affecting 1% to 1.5% of the population in the developed world. Projected data from the population-based studies suggest that the prevalence of AF will grow at least 3-fold by 2050. The health and economic burden imposed by AF and AF-related morbidity is enormous. Atrial fibrillation has a multiplicity of causes ranging from genetic to degenerative, but hypertension and heart failure are the commonest and epidemiologically most prevalent conditions associated with AF as both have been shown to create an arrhythmogenic substrate. Several theories emerged regarding the mechanism of AF, which can be combined into two groups: the single focus hypothesis and the multiple sources hypothesis. Several lines of evidence point to the relevance of both hypotheses to the mechanism of AF, probably with a different degree of involvement depending on the variety of AF (paroxysmal or persistent). Sustained AF alters electrophysiological and structural properties of the atrial myocardium such that the atria become more susceptible to the initiation and maintenance of the arrhythmia, a process known as atrial remodeling. Angiotensin II has been recognized as a key element in atrial remodeling in association with AF opening the possibility of exploitation of "upstream" therapies to prevent or delay atrial remodeling. The clinical significance of AF lies predominantly in a 5-fold increased risk of stroke. The limitations of warfarin prompted the development of new antithrombotic drugs, which include anticoagulants, such as direct oral thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban). Novel mechanical approaches for the prevention of cardioembolic stroke have recently been evaluated: percutaneous left atrial appendage occluders, minimally invasive surgical isolation of the left atrial appendage, and implantation of carotid filtering devices.
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PMID:Update on atrial fibrillation: part I. 1825 25

Atrial fibrillation (AF) requires anticoagulation for prevention of arterial embolism, especially in the presence of defined risk factors summarized in the CHADS (2) score (congestive heart disease, hypertension, age >75 years, diabetes, history of ischemic stroke or transient cerebral ischemia). Vitamin K antagonists as drugs of choice have several limitations. International normalized ratio (INR) adjustment to 2.0 to 3.0 may be difficult to maintain, and doses vary widely between patients. Inherited variations of the vitamin K epoxide reductase C1 enzyme and of the cytochrome P450 2C9 system influence the dosage as well as exogenous factors such as food and drug intake or intercurrent diseases. Increasing age and risk of falling are the main factors behind the underuse of anticoagulation in AF. Anticoagulants with a lack of all or most of these characteristics and without need of regular monitoring for dose adjustment may improve the adherence to the indication for anticoagulation. Indirect systemic and oral direct factor Xa and oral direct thrombin inhibitors are currently being developed for the prevention of embolism in patients with AF.
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PMID:New anticoagulants in atrial fibrillation. 1978 62

The proteinase-activated receptor 2 (PAR-2) expression is increased in endothelial cells derived from women with preeclampsia, characterized by widespread maternal endothelial damage, which occurs as a consequence of elevated soluble vascular endothelial growth factor receptor-1 (sVEGFR-1; commonly known as sFlt-1) in the maternal circulation. Because PAR-2 is upregulated by proinflammatory cytokines and activated by blood coagulation serine proteinases, we investigated whether activation of PAR-2 contributed to sVEGFR-1 release. PAR-2-activating peptides (SLIGRL-NH(2) and 2-furoyl-LIGRLO-NH(2)) and factor Xa increased the expression and release of sVEGFR-1 from human umbilical vein endothelial cells. Enzyme-specific, dominant-negative mutants and small interfering RNA were used to demonstrate that PAR-2-mediated sVEGFR-1 release depended on protein kinase C-beta(1) and protein kinase C-epsilon, which required intracellular transactivation of epidermal growth factor receptor 1, leading to mitogen-activated protein kinase activation. Overexpression of heme oxygenase 1 and its gaseous product, carbon monoxide, decreased PAR-2-stimulated sVEGFR-1 release from human umbilical vein endothelial cells. Simvastatin, which upregulates heme oxygenase 1, also suppressed PAR-2-mediated sVEGFR-1 release. These results show that endothelial PAR-2 activation leading to increased sVEGFR-1 release may contribute to the maternal vascular dysfunction observed in preeclampsia and highlights the PAR-2 pathway as a potential therapeutic target for the treatment of preeclampsia.
Hypertension 2010 Mar
PMID:Activation of proteinase-activated receptor 2 stimulates soluble vascular endothelial growth factor receptor 1 release via epidermal growth factor receptor transactivation in endothelial cells. 2012 8

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. The prevalence and incidence of AF are rising, as confirmed in several European and American registries. Guidelines published in 2008 from the European Society of Cardiology/American Heart Association and from the American College of Chest Physicians, clarified the strategy of antithrombotic treatment in AF, which is based on the presence of risk factors for thromboembolism. This approach allows physicians to classify patients as at low, moderate or high risk, according to their individual risk characteristics, which are relatively similar in both sets of recommendations. Patients at moderate risk, however, who might justify anticoagulant or antiplatelet treatment, could be better characterized using morphological (echocardiographic) and/or biological factors or risk markers. Recent data have shown that the existence of a thrombogenic milieu in the left atrium (e.g., dilatation of the left atrial appendage and/or thrombus and/or spontaneous echocontrast and/or reduced emptying/filling flow velocity) indicates a higher risk of embolism and mortality. Furthermore, high-sensitivity C-reactive protein and haemostasis markers of coagulation are associated with thromboembolic risk and excess mortality in AF. Although current recommendations for the management of AF are not based on such markers, both could help physicians choose the optimal antithrombotic treatment (either vitamin K antagonists or antiplatelet drugs) according to the patient's specific risk profile. Nowadays, registries confirm under-prescription of vitamin K antagonist treatment in the 'real world,' even in patients at high thromboembolic risk, and over-prescription for at least one-third of low-risk patients. It is crucially important to realize that the risk of bleeding in patients with risk factors (e.g., older age, hypertension) is close to the risk of thromboembolism, which can have devastating outcomes in patients in AF. Alternative and efficient strategies (new oral anticoagulants, non-surgical closure of the left atrial appendage using percutaneous devices) are currently under investigation. Therefore reducing the risk of thromboembolism should be physicians' primary aim, particularly with the advent of alternative treatments and the development of new antithrombotic drugs such as oral thrombin and factor Xa inhibitors, which are currently being evaluated in clinical trials.
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PMID:Should all patients with non-valvular atrial fibrillation be anticoagulated? 2036 47

Atrial fibrillation (AF) is the most common clinically relevant cardiac arrhythmia. Prevalence and incidence rates are rising with the advancing population age. A severe complication of untreated AF is thrombus formation in the left atrial appendage with consecutive peripheral thromboembolism. Thus, AF is a major contributor to thromboembolic events, especially in the elderly. Depending on the CHADS2 score for thromboembolic events that takes into account congestive heart failure, hypertension, age, diabetes mellitus and stroke as risk factors, oral anticoagulation therapy with vitamin K antagonists is currently the treatment of choice for the prevention of thromboembolism. However, due to drawbacks of current anticoagulation therapy new substances for oral therapy are currently evaluated in various clinical studies. This article provides an up to date overview of orally active compounds for the future treatment of AF. Emphasis lies on comparison of direct thrombin inhibitors with factor Xa inhibitors that are currently investigated in clinical phase III studies for the treatment of non-valvular AF. The direct thrombin inhibitor dabigatran will be compared with factor Xa inhibitors like rivaroxaban and apixaban. Other promising agents currently investigated in phase II trials such as direct factor Xa inhibitors DU-176b (edoxaban) and YM150, will also be discussed.
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PMID:Update on pharmacologic approaches to prevent thromboembolism in atrial fibrillation: are thrombin and factor Xa inhibitors the ultimate answer? 2114 66

We can estimated the probability of developing thromboembolic disease and consequently prescribed antithrombotic measures to patients undergoing surgery. The anticoagulants carry the risk of abnormal bleeding, which can sometimes be fatal. Recently, this concept changed with the development of new drugs that retain their antithrombotic activity but decrease their anticoagulant effect; other advantages are: route of administration, predictable bioavailability (generally do not require monitoring), and little interaction with food and other drugs. The most representative are direct factor Xa inhibitors like apixaban and rivaroxaban as well as factor IIa inhibitors, such as dabigatran. They had been evaluated in patients undergoing hip or knee surgery in comparison with low molecular weight heparins; in general they had better results in efficacy and similar results in safety. Trials are now underway to evaluate their use in other surgical and nonsurgical environments. Today, the surgical patient is older and has comorbidities, such as atrial fibrillation, prosthetic valves, diabetes mellitus, hypertension, and other chronic diseases. These patients need be protected from thrombosis with low bleeding risk. New antithrombotic drugs offer a margin of safety and maintain efficacy; therefore, they constitute an advantage over classical anticoagulant drugs. We highlight concepts related with the need for thromboprophylaxis and the new antithrombotic medication in a surgical context.
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PMID:[The new oral anticoagulants in surgery]. 2198 89


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