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)

The existence of an association between idiopathic intracranial hypertension (IIH) and coagulation disorders in men was assessed prospectively. Microthrombi, associated with thrombophilia-hypofibrinolysis, occlude arachnoid sinus villi, thus reducing resorption of cerebrospinal fluid, leading to IIH. Ten consecutively referred men with IIH, nine whites, one African American, median age 36 years, were 2 to 1 matched by age and race by healthy male controls. Polymerase chain reaction assays were done for four thrombophilic and one hypofibrinolytic gene mutations: G1691A factor V Leiden, G20210A prothrombin, C677T MTHFR, platelet glycoprotein IIb/IIIa (PL A1/A2), and 4G/5G polymorphism of the plasminogen activator inhibitor (PAI-1) gene promoter. Coagulation measures in plasma included dilute Russel's viper venom time (dRVVT), activated partial thromboplastin time (aPTT), the lupus anticoagulant, factor VIII, factor XI, plasminogen activator inhibitor activity (PAI-Fx), protein C antigenic, protein S total (antigenic), protein S free (antigenic), antithrombin III (functional), and resistance to activated protein C (RAPC). Tests performed on serum included anticardiolipin antibodies, homocysteine, and Lp(a). The body mass index was 40 kg/m(2) or greater (extremely obese) in two men, 30 to 40 kg/m(2) (obese) in three, and was 25 to 30 kg/m(2) in five (overweight). Cases differed from controls for inherited 4G4G homozygosity of the PAI-1 gene, four of 10 (40%) vs. one of 20 (5%), Fisher's p [p(f)]= .031, and for high levels (>21.1 U/mL) of the hypofibrinolytic PAI-1 gene product, PAI-Fx, 5 of 10 (50%) vs. one of 18 (6%), p(f) = .013. Thrombophilic factor VIII was high (> or = 150%) in three of 10 (30%) cases vs. zero of 16 (0%) controls, p(f)=. 046. The thrombophilic lupus anticoagulant was present in two of 10 (20%) cases vs. zero of 32 (0%) controls, p(f) = .052. Heritable hypofibrinolysis and heritable and acquired thrombophilia appear, speculatively, to be treatable etiologies of IIH in men. Understanding contributions of hypofibrinolysis and thrombophilia to the development of IIH should facilitate development of novel new approaches to treat this often-disabling neurologic disorder.
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PMID:Idiopathic intracranial hypertension: associations with thrombophilia and hypofibrinolysis in men. 1624 70

The role of thrombophilia in the pathogenesis of preeclampsia is controversial. The aim of this case-controlled study was to determine whether thrombophilia increases the risk of preeclampsia or interferes with its clinical course. A total of 808 white patients who developed preeclampsia (cases) and 808 women with previous uneventful pregnancies (controls) matched for age and parity were evaluated for inherited and acquired thrombophilia (factor V Leiden; factor II G20210A; methylenetetrahydrofolate reductase C677T; protein S, protein C, and antithrombin III deficiency; anticardiolipin antibodies; lupus anticoagulant; and hyperhomocysteinemia). Odds ratios (ORs) with 95% confidence intervals (CIs) for risk of being carriers of thrombophilia in cases compared with controls and for risk of maternal life-threatening complications and adverse perinatal outcomes in preeclamptic patients with or without thrombophilia were calculated. Women with severe preeclampsia (406 cases) had a higher risk (OR, 4.9; 95% CI, 3.5 to 6.9) of being carriers of either an inherited or acquired thrombophilic factor, except for protein S, protein C, and antithrombin deficiency. In women with mild preeclampsia (402 cases), only prothrombin and homozygous methylenetetrahydrofolate reductase gene mutations were significantly more prevalent than in the controls. Thrombophilic patients with severe preeclampsia are at increased risk of acute renal failure (OR, 1.8; 95% CI, 1.5 to 2.2), disseminated intravascular coagulation (OR, 2.7; 95% CI, 1.1 to 6.4), abruptio placentae (OR, 2.6; 95% CI, 1.2 to 6.0) and perinatal mortality (OR, 1.7; 95% CI, 1.5 to 2.2) compared with nonthrombophilic preeclamptic patients. Our study demonstrates a significant association between maternal thrombophilia and severe preeclampsia in white women. Thrombophilia also augments the risk of life-threatening maternal complications and adverse perinatal outcomes in preeclamptic patients.
Hypertension 2005 Dec
PMID:Thrombophilia is significantly associated with severe preeclampsia: results of a large-scale, case-controlled study. 1628 82

Angiogenesis, a complex, coordinated process resulting in the assembly and maturation of new blood vessels, is critical for the growth of tumors. Several lines of evidence argue for angiogenesis inhibition in the treatment of colorectal cancer (CRC) : 1) angiogenesis (as measured by microvessel count), and the expression of pro-angiogenesis factors, such as vascular endothelial growth factor (VEGF), the key regulator of normal and pathological angiogenesis, have been reported to correlate with advanced disease and a worse prognosis ; 2) the expression of VEGF has been shown to correlate with RAS mutations, alterations in the APC-WNT signaling pathway, and overexpression of cyclo-oxygenase-2, which all are frequent in CRC ; 3) bevacizumab, a humanized anti-VEGF monoclonal antibody, is a potent inhibitor of tumor growth of various CRC cell lines in murine xenografts ; 4) the addition of bevacizumab to systemic chemotherapy has been shown to be significantly superior to chemotherapy alone in terms of objective tumor response rate, progression-free survival, and overall survival in patients with metastatic CRC, in the frontline, and more recently in the second-line setting, without worsening of chemotherapy-related toxicity. However, several potential specific adverse events, such as thrombosis, hemorrhages, proteinuria, arterial hypertension, and bowel perforations have been described. Whether the antitumoral efficacy of bevacizumab could be increased when combined to low-dose (metronomic) chemotherapy, or radiotherapy (in rectal cancer), is under development, as well other VEGF-targeted approaches (e.g., dominantnegative mutants, antisense oligonucleotides, antibodies directed against VEGF receptors (VEGFR), VEGFR tyrosine kinase inhibitors, soluble VEGFR,...), or other anti-angiogenesis agents (e.g., thalidomide, celecoxib, angiozyme...).
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PMID:[Therapeutic strategies using VEGF inhibitors in colorectal cancer]. 1638 67

Increased blood pressure induces functional and structural changes of the vascular endothelium. Depression of endothelium-dependant vasodilatation is an early manifestation of endothelial dysfunction due to hypertension. It can be demonstrated by pharmacological or physiological tests. Decreased availability of nitric oxide (NO) is a major determinant of the depression of vasodilatation. It may be caused by a reduction in the activity of NO-endothelial synthase (NOSe) related to: 1) a deficit in substrate (L-arginine), 2) an inhibition by asymmetrical dimethylarginine, 3) a deficit in the cofactor tetrahydrobiopterin (BH4). However, the increase in oxidative stress, a producer of superoxide radicals which combine with NO to form peroxynitrates (ONOO-), is the determining factor. It is related to activation of membranous NAD(P)H oxidases initiated by the stimulation of activating mecanosensors of protein C kinase. The message is amplified by oxidation of BH4 which transforms the NOSe into a producer of superoxide radicals. A cascade of auto-amplification loops leading to atherosclerosis and its complications is then triggered. The superoxide radicals and the peroxynitrates oxidise the LDL-cholesterol. They activate the nuclear factor-kappaB which controls the genes stimulating the expression of many proteins: angiotensinogen and AT1 receptors which stimulate the sympathetic system, receptors of oxidised LDL, adhesion and migration factors (ICAM-1, VCAM-1, E-selectin and MCP-1), pro-inflammatory cytokins (interleukines and TNF-alpha), growth factors (MAP kinases), plasminogen activator inhibitor 1. The monocytes and smooth muscle cells produce metalloproteinases and pro-inflammatory cytokins which destabilise the atheromatous plaque and favourise vascular remodelling. Inshort, the endothelial dysfunction due to hypertension plays a role in a complex physiopathological process and is a marker of future cardiovascular events.
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PMID:[Hypertension, endothelial dysfunction and cardiovascular risk]. 1710 Jan 43

Thrombophilia may be defined as an acquired or congenital abnormality of hemostasis predisposing to thrombosis. Because arterial thrombosis is usually linked with classical risk factors such as smoking, hypertension, dyslipidemia, or diabetes, a thrombophilia workup is usually not considered in case of arterial thrombosis. The most accepted inherited hemostatic abnormalities associated with venous thromboembolism are factor V Leiden (FVL) and factor II (FII) G20210A mutations, as well as deficiencies in antithrombin (AT), protein C (PC), and protein S (PS). This review focuses on the link between these abnormalities and arterial thrombosis. Overall, the association between these genetic disorders and the three main arterial complications (myocardial infarction [MI], ischemic stroke [IS], and peripheral arterial disease [PAD]) is modest. Routine screening for these disorders is therefore not warranted in most cases of arterial complications. However, when such an arterial event occurs in a young person, inherited abnormalities of hemostasis seem to play a role, particularly when associated with smoking or oral contraceptive use. These abnormalities also seem to play a role in the risk of premature occlusion after revascularization procedures. Therefore thrombophilia tests may be informative in a very restricted population with arterial events. Anticoagulants rather than antiplatelet therapy may be preferable for these patients, although this remains to be proven.
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PMID:Inherited thrombophilia in arterial disease: a selective review. 1743 3

Multiorgan dysfunction ensuing from severe heatstroke includes hypotension, hepatic and renal failure, hypercoagulable state, activated inflammation, and cerebral ischemia and injury. We attempted to assess whether human umbilical cord blood-derived CD34+ cell therapy improves survival during experimental heatstroke by attenuating multiorgan dysfunction. Anesthetized rats, immediately after the onset of heatstroke, were divided into 2 major groups and given CD34- or CD34+ cells (1 x 10(5)-5 x 10(5)/mL/kg body weight) i.v. They were exposed to ambient temperature of 43 degrees C to induce heatstroke. Another group of rats were exposed to room temperature (26 degrees C) and used as normothermic controls. Hypotension, hepatic and renal failure (evidenced by increased serum urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels in plasma), hypercoagulable state (evidenced by increased prothrombin time, activated partial thromboplastin time, and D-dimer, and decreased platelet count and protein C in plasma), activated inflammation (evidence by increased TNF-alpha levels in serum), and cerebral dysfunction (evidenced by intracranial hypertension, cerebral hypoperfusion and hypoxia, and cerebral ischemia and injury) were monitored. When the CD34- cell-treated or untreated rats underwent heat stress, their survival time values were found to be 19 to 23 min. Resuscitation with CD34+ cells significantly improved survival time (duration, 63-291 min). As compared with normothermic controls, all CD34- cell-treated heatstroke animals displayed hypotension, hepatic and renal failure, hypercoagulable state, activated inflammation, and cerebral ischemia and injury. However, CD34+ cell therapy significantly caused attenuation of all the above-mentioned heatstroke reactions. In addition, the levels of IL-10 in plasma and glial cell line-derived neurotrophic factors in brain were all significantly increased after CD34+ cell therapy during heatstroke. Our data indicate that CD34+ cell therapy may resuscitate persons who had a heatstroke by reducing multiorgan dysfunction or failure.
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PMID:Human umbilical cord blood-derived CD34+ cells cause attenuation of multiorgan dysfunction during experimental heatstroke. 1750 7

Hyperbaric oxygen has been found to be beneficial in treating heatstroke animals. We attempted to further assess the possible mechanism of therapeutic protection offered by hyperbaric oxygen in experimental heatstroke. Anesthetized rats, immediately after the onset of heatstroke, were randomized into the following groups and given: a) hyperbaric oxygen (100% O(2) at 253 kPa for 1 h); or b) normal air. They were exposed to 43 degrees C temperature to induce heatstroke. When the untreated rats underwent heat stress, their survival time values were found to be 20-24 min. Resuscitation with hyperbaric oxygen increased the survival time to new values of 152-176 min. All untreated heatstroke rats displayed cerebrovascular dysfunction (evidenced by hypotension, intracranial hypertension, and cerebral hypoperfusion, hypoxia, and ischemia), hypercoagulable state (evidenced by increased levels of activated partial thromboplastin time, prothrombin time, and D-dimer, but decreased values of platelet count and protein C in plasma), and tissue ischemia/injury (evidenced by increased levels of creatinine, serum urea nitrogen, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase in plasma, and dihydrobenzoic acid, lipid peroxidation, and oxidized-form glutathione/reduced-form of glutathione ratio in hypothalamus). The cerebrovascular dysfunctions, hypercoagulable state, tissue ischemia/injury, and brain oxidative stress that occurred during heatstroke were all suppressed by hyperbaric oxygen therapy. The current results indicate that hyperbaric oxygen therapy may resuscitate rats that had a heatstroke by decreasing multiple organ dysfunction and brain oxidative stress.
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PMID:Hyperbaric oxygen improves survival in heatstroke rats by reducing multiorgan dysfunction and brain oxidative stress. 1750 57

Asthma control is a key point in patient management. GINA's most recent report emphasises the need to investigate uncontrolled asthma, of which non-compliance with treatment, COPD, smoking, chronic sinusitis, gastroesophageal reflux disease and obesity are the usual causes. The aim of this work is to evaluate the role of pulmonary thromboembolism (PTE) in cases of difficult- -to-treat asthma. We reviewed the case reports of patients with severe persistent asthma followed in our Asthma Outpatients Clinic between 2004 and 2006. We selected the ones that maintained uncontrolled disease despite an optimal therapeutical approach and investigated the causes. In this group (n=254), 28 (11%) had severe persistent asthma and their mean age was 44 +/- SD18 years old. 86% were females. Of these, 57% (n=16) had uncontrolled disease: 35% (n=6) due to non-compliance with treatment; 29% (n=5) pulmonary thrombombolism (scintigraphic confirmation); 12% (n=2) severe rhinosinusitis; 6% (n=1) hypereosinophilic syndrome; 6% (n=1) persistent allergen exposure and 6% (n=1) are still being investigated. Patients with TPE (mean age 56 +/- SD9 years old; 80% females; 80% Caucasians) were diagnosed with asthma as adults (mean age 37 +/- SD14 years old). The mean time until the diagnosis of TPE was 18 +/- SD12 years. Predisposing factors for TPE were venous insufficiency (40%), hypertension (40%) and deficit of functional protein C and S (20%). All these patients received anticoagulant therapy (80% are still medicated). It should be noted that after the beginning of anticoagulants, 40% of the patients achieved control of their asthma and 40% have partially controlled disease. There were no hospital admissions for asthma exacerbations after the beginning of anticoagulation in this group. This study supports the inclusion of TPE in the group of comorbidities to consider while investigating uncontrolled asthma.
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PMID:[Pulmonary embolism and difficult-to-treat asthma]. 1818 29

Inherited thrombophilic disorders are a well-recognized risk factor for systemic thromboembolism. These disorders include deficiencies of anticoagulant proteins such as protein C, protein S, and antithrombin III, abnormalities of factor V and prothrombin resulting from genetic mutations, and hyperhomocysteinemia. Except for hyperhomocysteinemia, which has been associated with both venous and arterial thrombosis, the other heritable disorders primarily cause venous thromboembolism. We have reviewed the association between heritable thrombophilia and the development of thrombosis in the eye. The available literature consists of case-control studies and case reports. Preliminary data suggest a relationship between thrombotic disorders of the eye and the inherited hypercoagulable states. Some reports show a risk of thrombosis with the presence of factor V Leiden and hyperhomocysteinemia but these associations frequently disappear upon multivariate analysis. It is possible that inherited thrombophilia plays a supportive role to well-established risk factors such as hypertension and diabetes. Larger, well-designed studies will be necessary to clearly define the role of inherited thrombophilia in the development of thrombotic disorders of the eye.
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PMID:Inherited thrombophilia and the eye. 1832 Apr 77

Management of acute coronary syndromes, particularly unstable angina, acute myocardial infarction and non-Q-wave myocardial infarction, is one of the most common and costly problems facing modern medicine. Furthermore, the increasing availability of new research and clinical information relevant to the treatment of these conditions means that continuing reappraisal of management strategies is necessary. Accordingly, the Ushuaia conference, Tierra Del Fuego, Argentina, was convened to discuss current approaches and future treatment prospects for patients with these conditions. The conference was comprised of leading Argentinian cardiologists whose primary aim was to formulate consensus recommendations regarding the management of patients with acute coronary syndromes. The first of the major recommendations for the pharmacological management of acute coronary syndromes arising from the Ushuaia Consensus Conference was that aspirin (200 to 500mg initially, then 100 to 325 mg/day) should be administered to all patients except those for whom aspirin is absolutely (or relatively, depending on the clinician's discretion) contraindicated. In such cases, ticlopidine is a suitable alternative. Intravenous nitrates are indicated for patients with angina pain (24 to 48 hours' duration), ECG changes, recurrence of angina, or signs of heart failure; in other cases, oral, transdermal or sublingual nitrates may be administered. Use of beta-blockers is recommended except when absolutely contraindicated or when there is a strong suspicion of vasospasm as a dominant mechanism in angina. Intravenous administration of these agents is preferred in patients with tachycardia, arterial hypertension or angina. Calcium antagonists are generally not recommended as first choice therapy, but can be indicated (preferably using agents that decrease heart rate) when beta-blockers are contraindicated or when there is a strong suspicion of vasospasm as a dominant mechanism in angina. Calcium antagonists are also useful in combination with other drugs in patients with high blood pressure or treatment-refractory recurrent angina. Subcutaneous low molecular weight heparins and intravenous unfractionated heparin provide similar results and are indicated in a number of clinical situations. Emergency videocoronary angiography (VCA) is indicated in patients with persistent clinical and haemodynamic instability, recurrent ischaemia with heart failure, and refractory angina. Patients should also be referred for VCA if they have signs of left ventricular dysfunction, post-acute myocardial infarction angina with ECG changes, or ischaemia during functional studies. Post-VCA treatment will be determined by anatomical findings during VCA. Future prospects in the management of acute coronary syndromes include the development of more accurate prognostic markers and means of stratifying risk, such as sophisticated ECG criteria, serum markers of necrosis (e.g. troponin T and I), markers of thrombosis (e.g. D-dimer and fibrinopeptide A levels), markers of inflammation (e.g. reactive protein C, cell adhesion receptor expression, neopterine), and markers of 'good' prognosis (e.g. interleukin-10). Other pharmacological approaches under investigation include platelet IIb/IIIa receptor antagonists, clopidogrel and hirudin. Novel agents, such as anti-Xa, pentasaccharide, anti-tissue factor compounds, Ib receptor-blocking agents, agents that influence vascular endothelium and control cellular acidosis (e.g. HOE 642), macrolide antibiotics, HLA-DR system blockers and fusion compounds, are also in various stages of investigation or development.
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PMID:Current treatment and future prospects for the management of acute coronary syndromes: consensus recommendations of the 1997 ushuaia conference, tierra del fuego, Argentina. 1837 Apr 92


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