thromboplastin and Hypertension

This review article summarizes the role of coagulation in the pathogenesis of hypertension. It specifically focuses on significant factors and markers associated with coagulation, including D-dimer, fibrinogen and fibrin, prothrombin, P-selectin, soluble urokinase plasminogen activator receptor, thrombomodulin, tissue factor, tissue plasminogen activator, von Willebrand factor, β-thromboglobulin, and Stuart-Prower factor.. D-dimer levels were elevated in hypertensive individuals compared to healthy controls, and the levels increased with the severity of hypertension. These findings indicate that increased coagulation activity of fibrin plays a role in the development of thromboembolic complications in hypertensive patients. Additionally, both fibrinogen levels and D-dimer levels displayed a positive correlation with the duration of hypertension, suggesting that these biomarkers were positively associated with the length of time an individual had been hypertensive. Increased systolic and diastolic blood pressures have been linked to higher levels of prothrombin time and activated partial thromboplastin time in individuals with hypertension as well as those with normal blood pressure. Also, the presence of P-selectin, produced by activated platelets and endothelial cells during angiotensin II stimulation, played a role in the development of cardiac inflammation and fibrosis associated with hypertension. Moreover, the change in systolic blood pressure was associated with baseline soluble urokinase plasminogen activator receptor (suPAR) in hypertensive participants, and the change in suPAR levels was associated with the development of hypertension. Moreover, it was observed a decrease in thrombomodulin expression in the placenta of preeclamptic patients, suggesting its potential involvement in placental dysfunction, possibly driven by an imbalance in angiogenic factors. Tissue factors and autophagy might have significant implications in the pathogenesis of chronic thromboembolic pulmonary hypertension, particularly in the context of vascular remodelling. Likewise, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) might be a promising biomarker for the early detection of pulmonary arterial hypertension and the von Willebrand factor is a candidate prognostic biomarker. The arterial β-thromboglobulin levels were significantly lower than venous levels. This article concludes that D-dimer, fibrinogen and fibrin, prothrombin, P-selectin, soluble urokinase plasminogen activator receptor, thrombomodulin, tissue factor, tissue plasminogen activator, von Willebrand factor, and β-thromboglobulin are important factors involved in the pathogenesis of hypertension.

Topics: beta-Thromboglobulin; Biomarkers; Endothelial Cells; Female; Fibrinogen; Humans; Hypertension; P-Selectin; Placenta; Pregnancy; Prothrombin; Receptors, Urokinase Plasminogen Activator; Thrombomodulin; Thromboplastin; Tissue Plasminogen Activator; von Willebrand Factor

Tissue factor is the primary initiator of coagulation cascade and plays an essential role in haemostasis and thrombosis. In addition, tissue factor and coagulation proteases contribute to many cellular responses via activation of protease activated receptors. The heart is an organ with high levels of constitutive tissue factor expression. This review focuses on the role of tissue factor, coagulation proteases and protease activated receptors in heart haemostasis and the pathological heart remodelling associated with myocardial infarction, viral myocarditis and hypertension.

Topics: Animals; Blood Coagulation Factors; Fibrosis; Heart Valve Diseases; Hemostasis; Humans; Hypertension; Hypertension, Pulmonary; Hypertrophy; Models, Cardiovascular; Myocardial Infarction; Myocarditis; Myocytes, Cardiac; Receptors, Proteinase-Activated; Renin-Angiotensin System; Thromboplastin; Ventricular Remodeling

Tissue factor (TF), the physiologic initiator of blood coagulation, may contribute to the increased risk of thrombotic complications that characterizes arterial hypertension, as suggested by hypertensive animal models showing evidence for TF activation, and clinical studies in hypertensive patients at higher cardiovascular risk with increased circulating levels of TF and thrombogenic microparticles. Angiotensin II stimulates TF expression both in vitro and in vivo, an effect abolished by ACE or angiotensin II receptor inhibition. Moreover, renin-angiotensin system blockers, including aliskiren, a direct renin inhibitor, are able to modulate TF expression in monocytes and vascular endothelial cells activated by inflammatory cytokines. This behavior is suggestive of anti-inflammatory and anti-thrombotic properties of renin-angiotensin system blockers, and is compatible with the possibility that blocking local renin-angiotensin system activation might downregulate TF, thus reducing the risk of ischemic complications in hypertensive patients.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Endothelium, Vascular; Humans; Hypertension; Renin; Renin-Angiotensin System; Risk Factors; Thromboplastin; Thrombosis

Systemic hypertension, a pathological process to which the renin-angiotensin system contributes importantly, is characterized by a thrombophilic diathesis and an increased risk for acute ischemic coronary events. That apparently contradictory profile might, to some extent, relate to the modulating properties of Angiotensin II, the effector arm of the renin angiotensin system, on tissue factor expression, the physiologic initiator of blood coagulation and a basic mechanism in the pathogenesis of acute thrombosis. In fact, monocytes and macrophages within the atherosclerotic plaque as well as inflamed vascular endothelial cells may locally synthesize Angiotensin II. In turn, the peptide, by binding to its specific membrane receptors, activates a series of intracellular signals eventually converging upon NF-kappaB, a transcription factor that upregulates tissue factor expression. Drugs interfering with the renin-angiotensin system, either by inhibiting conversion of Angiotensin I to Angiotensin II or by blocking its receptors, have the potential to inhibit tissue factor expression and to modulate its procoagulant effect. This property may contribute to the protection exerted by renin-angiotensin blockers from acute ischemic events in patients with hypertension and other cardiovascular diseases.

Topics: Angiotensin II; Animals; Cardiovascular System; Humans; Hypertension; NF-kappa B; Renin-Angiotensin System; Thromboplastin

Tissue factor is a key enzyme in coagulation process. It is primary known as a cofactor for factor VIIa-mediated triggering of blood coagulation, which proceeds in a cascade of extracellular reactions. Tissue factor forms a catalytic complex with VIIa and intitiates coagulation by activating factor IX and X, ultimately resulting in thrombin formation. Being a transmembranic glycoprotein it takes a signalling information to another cell activity after endothelium or other tissue damage. Tissue factor plays a pivotal role in blood clotting physiology and pathology especialy in atherothrombosis. Thrombogenic tissue factor on cell-derived microparticles is present in the circulating blood of patients with acute coronary syndromes. Tissue factor is found in adventitia of blood vessels and the lipid core of atherosclerotic plaques (but not in vascular cells contacting directly with blood). Although the molecular mechanisms responsible for these phenomena remain unclear, it is thought that they are brought about by the action of intracellular signaling, resulting in gene transcription and subsequent protein synthesis. By expressing on monocyte or macrofage cell membrane surface it is involved in proinflammatory action and plaque destabilisation. This shifted the emphasis to investigations of what happened on the cell surface, and later to the cell biology of tissue factor and its inducibility in monocytes/macrophages and endothelial cells. Recent studies have suggested that tissue factor also plays non-hemostatic roles in blood vessel development, tumor angiogenesis and metastasis, inflamation. Tissue factor upregulates a number of genes involved in regulation of growth, transcription, and cellular motility, as well as cytokines, makes it possible to suggest a link between the formation of the tissue factor / VIIa complex and the cellular processes. Regulation of tissue factor activity by natural tissue factor pathway inhibitor (synthesized by vascular endothelial cells) or by special drugs is a new insight in thrombosis and vessel reocclusion preventive therapy. Tissue factor concentration in circulating blood has a higher informativity comparing to troponine and CRB values.

Topics: Age Factors; Aged; Arteriosclerosis; Blood Coagulation; C-Reactive Protein; Diabetes Complications; Female; Humans; Hypercholesterolemia; Hypertension; Male; Myocardial Infarction; Risk Factors; Sex Factors; Syndrome; Thromboplastin; Thrombosis; Troponin T

Angiotensin receptor blockers (ARBs) are widely used for the treatment of hypertension. It has been reported that the ARB losartan has antiplatelet, anticoagulant and profibrinolytic effects experimentally. These properties could be desirable to treat hypertensive patients with high atherothrombotic and/or thromboembolic risk. To examine the antithrombotic effects of losartan in hypertension, 20 consecutive patients with hypertension complicated by atrial fibrillation (AF) were enrolled in this study. The patients were treated with losartan 50 mg for 8 weeks followed by 100 mg for 4 weeks. Blood samples were obtained from each patient at 0 (pretreatment), 8 and 12 weeks after initiating treatment. Platelet aggregability, plasma levels of tissue factor (TF) and type 1 plasminogen activator inhibitor (PAI-1) activity levels were measured. The area under the curve for small platelet aggregability decreased from 100 to 42.8% at 12 weeks (P<0.0001). TF levels (ng ml(-1)) and PAI-1 activity (IU ml(-1); mean±s.d.) also changed from 14.2±3.6 to 10.9±4.5 at 12 weeks (P=0.0299) and from 11.7±3.6 to 8.5±3.1 at 12 weeks (P=0.0122), respectively. Losartan inhibited platelet activity and coagulation factors in a dose- and time-dependent manner in patients with hypertension complicated by AF, whereas the fibrinolytic capacity was increased. The use of losartan could be advantageous in the treatment of hypertensive patients with high atherothrombotic risk.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Atrial Fibrillation; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Humans; Hypertension; Losartan; Male; Middle Aged; Pilot Projects; Plasminogen Activator Inhibitor 1; Platelet Aggregation; Risk Factors; Thromboembolism; Thromboplastin; Time Factors; Treatment Outcome

Abnormalities in endothelial function, angiogenesis and thrombogenesis are found in essential hypertension. Angiotensin II has been postulated as an agent involved in these processes. We hypothesized that the treatment of essential hypertension with the angiotensin II receptor antagonist, losartan, would affect endothelial damage/dysfunction, angiogenesis and coagulation, when compared to treatment with a diuretic.. Forty hypertensive patients (28 male, mean age 56 +/- 11.8 years) were randomized to treatment with losartan 50-100 mg o.d. or hydrochlorothiazide 12.5-25 mg o.d. over a 12-week period. Patients were assessed at week 0, 4 and 12. Endothelial damage/dysfunction was assessed using plasma levels of von Willebrand factor (vWf) and changes in flow-mediated dilation of the brachial artery (FMD). Vascular endothelial growth factor (VEGF) and its soluble receptor Flt-1 (sFlt-1) were measured as indices of angiogenesis, and plasma tissue factor (TF) as an index of coagulation. Baseline results in hypertensives were compared to 20 healthy controls (13 male, mean age 61.1 +/- 10.1 years).. Mean patient BP was 161/95 +/- 21/18 mmHg compared to 134/81 +/- 11/7 mmHg in controls (p<0.002). Plasma levels of TF (p=0.023) were significantly higher in patients compared to controls, and FMD was significantly lower (p<0.001). There were no significant differences in baseline blood pressures, plasma indices or FMD between patients randomized to losartan and hydrochlorothiazide. There were no significant changes in levels of plasma indices or FMD over 12 weeks of treatment in either patient group. Significant correlations between levels of VEGF with sFlt-1 (Spearman p<0.001) and TF (p=0.009) and sFlt-1 and TF (p=0.035) were seen in the untreated state, amongst the patient group only.. We have confirmed previous observations of increased levels of TF and decreased FMD in hypertensive patients compared to healthy controls. Contrary to previous observations in higher-risk hypertensive patient groups, the treatment of essential hypertension with either losartan or hydrochlorothiazide did not affect indices of endothelial damage/dysfunction, angiogenesis or coagulation.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Diuretics; Endothelium, Vascular; Female; Humans; Hydrochlorothiazide; Hypertension; Losartan; Male; Middle Aged; Neovascularization, Pathologic; Sodium Chloride Symporter Inhibitors; Thromboplastin; von Willebrand Factor

Angiotensin II stimulates the expression of tissue factor (TF) and plasminogen activator inhibitor type-1 (PAI-1), and AT1 receptor blockade (ARB) reduces PAI-1 and TF activities in experimental studies. We investigated the effects of ARBs on TF activity, tissue plasminogen activator (tPA), PAI-1 antigen levels, plasma renin activity (PRA) and aldosterone levels in hypertensive patients. Placebo, losartan 100mg, irbesartan 300 mg, and candesartan 16 mg daily were administered to 122 patients for 2 months. Compared with placebo, ARBs significantly reduced TF activity (P <0.001 by ANOVA), and candesartan was the most potent. Compared with placebo or losartan, irbesartan and candesartan significantly lowered plasma levels of PAI-1 antigen (P <0.001 by ANOVA) with no differences between the two. Compared with placebo, all ARBs lowered plasma levels of aldosterone (P=0.012 by ANOVA) and increased PRA (P=0.005 by ANOVA). There were significant correlations between the degree of change in TF activity and PAI-1 antigen levels (r=0.458, P <0.0001) and between the change in TF activity and PRA (r=-0.296, P=0.006), but not with the magnitude of reduction in blood pressure following ARB therapy. ARBs significantly reduced TF activity, PAI-1 antigen levels, and aldosterone levels in hypertensive patients. The clinical significance of the varying potency of some ARBs needs to be further investigated.

Topics: Angiotensin II Type 1 Receptor Blockers; Double-Blind Method; Female; Fibrinolysis; Humans; Hypertension; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Renin-Angiotensin System; Thromboplastin

In this study, we investigated how platelets and aorta contribute to the creation and maintenance of a prothrombotic state in an experimental model of postmenopausal hypertension in ovariectomized rats.. Bilateral ovariectomy was performed in both 14-week-old female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. The animals were kept in phytoestrogen free diet. Vascular parameters, platelet, coagulation and aortic prothrombotic functions and mechanisms were assessed.. Exacerbated platelet aggregation was observed in both SHR and WKY animals after ovariectomy. The mechanism was related to aortic COX2 downregulation and reduction in AMP, ADP, and ATP hydrolysis in serum and platelets. A procoagulant potential was observed in plasma from ovariectomized rats and this was confirmed by kallikrein and factor Xa generation in aortic rings. Aortic rings derived from ovariectomized SHR presented a greater thrombin generation capacity compared to equivalent rings from WKY animals. The mechanism involved tissue factor and PAR-1 upregulation as well as an increase in extrinsic coagulation and fibrinolysis markers in aorta and platelets. Aortic smooth muscle cells pre-treated with a plasma pool derived from estrogen-depleted animals developed a procoagulant profile with tissue factor upregulation. This procoagulant profile was dependent on inflammatory signalling, since NFκB inhibition attenuated the procoagulant activity and tissue factor expression.. A prothrombotic phenotype was observed in both WKY and SHR ovariectomized rats being associated with platelet hyperreactivity and tissue factor upregulation in aorta and platelets. The mechanism involves proinflammatory signalling that supports greater thrombin generation in aorta and vascular smooth muscle cells.

Topics: Animals; Aorta; Estrogens; Female; Hypertension; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thrombin; Thromboplastin

Multicellular interactions of platelets, leukocytes, and the blood vessel wall support coagulation and precipitate arterial and venous thrombosis. High levels of angiotensin II cause arterial hypertension by a complex vascular inflammatory pathway that requires leukocyte recruitment and reactive oxygen species production and is followed by vascular dysfunction. We delineate a previously undescribed, proinflammatory coagulation-vascular circuit that is a major regulator of vascular tone, blood pressure, and endothelial function. In mice with angiotensin II-induced hypertension, tissue factor was up-regulated, as was thrombin-dependent endothelial cell vascular cellular adhesion molecule 1 expression and integrin α

Topics: Aged; Angiotensin II; Animals; Blood Coagulation; Blood Platelets; Blood Pressure; Factor XI; Female; Humans; Hypertension; Macrophage-1 Antigen; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Oligonucleotides, Antisense; Platelet Glycoprotein GPIb-IX Complex; Rats, Wistar; Thrombin; Thromboplastin; Vascular Cell Adhesion Molecule-1

Occlusive renovascular disease and hypertension may progress to CKD. Circulating levels of several biomarkers, including fibroblast growth factor (FGF)-23, Klotho, and soluble urokinase plasminogen activator receptor (suPAR), are altered in patients with CKD, but their role in essential hypertension (EH) and renovascular hypertension (RVH) remains unclear.. Levels of FGF-23, Klotho, suPAR, plasminogen activator inhibitor (PAI)-1, tissue factor, and tissue factor pathway inhibitor (TFI) were measured in the inferior vena cava and renal vein of hypertensive patients with atherosclerotic renal artery stenosis (n=12) or age-matched participants with EH (n=12) and relatively preserved renal function. Single-kidney blood flow was measured to calculate renal release of markers. For control, peripheral vein levels were measured in healthy volunteers (HVs; n=12).. FGF-23 levels did not differ among the groups, whereas Klotho levels were lower in participants with RVH and EH than in HVs, and suPAR levels were elevated in patients with RVH compared with HVs and patients with EH (6.1±1.5 versus 4.4±1.9 and 3.2±1.2 ng/ml, P<0.05). PAI-1 levels were higher in patients with RVH than in patients with EH, but tissue factor and TFI levels were not statistically significantly different. After adjustment for GFR, Klotho levels remained decreased in both RVH and EH, and suPAR and PAI-1 levels remained elevated in RVH. eGFR correlated inversely with systemic and renal vein suPAR levels, and directly with systemic Klotho levels.. Klotho levels are low in hypertensive patients, whereas suPAR and PAI-1 levels are specifically elevated in RVH, correlating with GFR. Klotho, PAI-1, and suPAR may be markers of kidney injury in hypertensive patients.

Topics: Aged; Atherosclerosis; Biomarkers; Cross-Sectional Studies; Essential Hypertension; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glomerular Filtration Rate; Glucuronidase; Humans; Hypertension; Hypertension, Renovascular; Klotho Proteins; Lipoproteins; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Prospective Studies; Receptors, Urokinase Plasminogen Activator; Renal Artery Obstruction; Renal Circulation; Renal Veins; Thromboplastin; Vena Cava, Inferior

The hypothesis that hypertension induces a hypercoagulable state arises from the complications associated with hypertension: stroke and myocardial infarction. Here, we determine whether hypertension causes changes in the thrombin-generating capacity of the vascular wall.. We used spontaneously hypertensive rats (SHR) compared with Wistar rats. The addition of thoracic aortic rings of SHR to a Wistar or SHR plasma pool resulted in a greater increase in thrombin generation compared with equivalent rings from Wistar. This increase occurred in 12- but not 5-week-old rats and was prevented by an angiotensin II-converting enzyme inhibitor, indicating that established hypertension is required to induce increased thrombin generation within the vessel wall. Whereas no difference was observed for endothelial cells, thrombin formation was higher on aortic smooth muscle cells (SMCs) from SHR than on those from Wistar. Exposure of negatively charged phospholipids was higher on SHR than on Wistar rings, as well as on cultured SMCs. Tissue factor activity was higher in SHR SMCs. Twelve-week-old SHR exhibited accelerated FeCl3-induced thrombus formation in carotid arteries, and the resulting occlusive thrombi were disaggregated by blockade of glycoprotein Ibα-von Willebrand factor interactions. SHR SMCs were more sensitive to thrombin-induced proliferation than Wistar SMCs. This effect was totally abolished by a protease-activated receptor 1 inhibitor.. The prothrombotic phenotype of the SHR vessel wall was due to the ability of SMCs to support greater thrombin generation and resulted in accelerated occlusive thrombus formation after arterial injury, which was sensitive to glycoprotein Ibα-von Willebrand factor inhibitors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta, Thoracic; Blood Coagulation; Blood Pressure; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Fibrinolytic Agents; Hypertension; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIb-IX Complex; Rats, Inbred SHR; Rats, Wistar; Receptor, PAR-1; Thrombin; Thromboplastin; Thrombosis; Time Factors; Vascular Remodeling; von Willebrand Factor

This study was designed to explore the role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, in platelet aggregation in hypertension and its possible mechanisms. Spontaneously hypertensive rats (SHR) and L-NAME-induced hypertensive rats were orally administered with L-arginine (1 g/(kg·day) for 14 days. Systolic blood pressure, platelet aggregation, and plasma tissue factor (TF) level and activity were measured. The plasma concentration of ADMA in SHR was determined. In vitro, platelet-rich plasma isolated from Wistar rats was prepared in order to observe the effect of exogenous ADMA on platelet aggregation and TF level and (or) activity in platelet-rich plasma. In both types of hypertensive rats, systolic blood pressure, platelet aggregation, and the level and activity of plasma TF were elevated compared with corresponding control animals. Plasma ADMA level was also increased in SHR. Treatment with L-arginine, a competitor of ADMA, lowered blood pressure and inhibited platelet aggregation concomitantly with a decrease in plasma TF level and activity in both types of hypertensive rats. We also found that exogenous ADMA promoted platelet aggregation and increased TF level and (or) activity in platelet-rich plasma, an effect that was inhibited by pretreatment with L-arginine. Importantly, the enhanced platelet aggregation induced by exogenous ADMA was reduced by pretreatment with anti-TF antibody. The results suggest that endogenous ADMA may be involved in platelet hyperaggregation status in hypertension, and the facilitation of platelet aggregation by ADMA is related to upregulation of the level and activity of plasma TF.

Topics: Animals; Arginine; Hypertension; Male; Platelet Aggregation; Random Allocation; Rats; Rats, Inbred WKY; Thromboplastin; Up-Regulation

In patients with arterial hypertension (AH) accompanied by abdominal obesity (AO) increase in platelets adhesive and aggregation functions was noted in vitro and in vivo. The cause of these disturbances is blood serum and platelets lipid peroxidation activation, increase in synthesis of Willebrand's factor in a vascular wall, and intensification of thromboxane production in platelets. Activation of thromboplastin production is the main cause of increase in blood coagulation in patients with AH and AO.

Topics: Adult; Blood Coagulation; Blood Platelets; Body Mass Index; Female; Humans; Hypertension; Lipid Peroxidation; Male; Malondialdehyde; Obesity, Morbid; Platelet Aggregation; Platelet Count; Thromboplastin; Thromboxanes; von Willebrand Factor

We have previously reported that Chinese traditional medicine rutaecarpine (Rut) produced a sustained hypotensive effect in phenol-induced and two-kidney, one-clip hypertensive rats. The aims of this study are to determine whether Rut could exert antihypertensive and anti-platelet effects in spontaneously hypertensive rats (SHR) and the underlying mechanisms. In vivo, SHR were given Rut and the blood pressure was monitored. Blood was collected for the measurements of calcitonin gene-related peptide (CGRP), tissue factor (TF) concentration and activity, and platelet aggregation, and the dorsal root ganglia were saved for examining CGRP expression. In vitro, the effects of Rut and CGRP on platelet aggregation were measured, and the effect of CGRP on platelet-derived TF release was also determined. Rut exerted a sustained hypotensive effect in SHR concomitantly with the increased synthesis and release of CGRP. The treatment of Rut also showed an inhibitory effect on platelet aggregation concomitantly with the decreased TF activity and TF antigen level in plasma. Study in vitro showed an inhibitory effect of Rut on platelet aggregation in the presence of thoracic aorta, which was abolished by capsazepine or CGRP(8-37), an antagonist of vanilloid receptor or CGRP receptor. Exogenous CGRP was able to inhibit both platelet aggregation and the release of platelet-derived TF, which were abolished by CGRP(8-37). The results suggest that Rut exerts both antihypertensive and anti-platelet effects through stimulating the synthesis and release of CGRP in SHR, and CGRP-mediated anti-platelet effect is related to inhibiting the release of platelet-derived TF.

Topics: Animals; Antihypertensive Agents; Blood Platelets; Blood Pressure; Calcitonin Gene-Related Peptide; Cardiotonic Agents; Hypertension; Indole Alkaloids; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Quinazolines; Random Allocation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboplastin; Vasodilator Agents

People with hypertension display an inflammatory pattern that includes increased plasma concentrations of monocyte chemoattractant protein 1 (MCP-1) and C-reactive protein (CRP) and enhanced expression of tissue factor (TF) mRNA in blood monocytes.. In this study, we investigated the relationship between CRP concentrations and TF and MCP-1 mRNA expression in unstimulated and lipopolysaccharide (LPS)-stimulated monocytes isolated from hypertensives with or without an increase in carotid intima-media thickness (IMT). We also investigated the expression of TF and MCP-1 mRNA and MCP-1 protein after in vitro addition of CRP to monocytes. We measured CRP (by immunonephelometry) and monocyte expression of TF and MCP-1 (by real-time PCR) in 80 untreated hypertensive patients without clinical cardiovascular disease (CVD) or additional risk factors for CVD compared with 41 controls. Based on IMT measured by carotid Doppler ultrasonography, patients were classified into the categories of normal (< or =1 mm) or abnormal (>1 mm). TF and MCP-1 mRNA and MCP-1 protein (by Western blotting) were measured after in vitro addition of CRP to monocytes from 10 randomized controls as well as 10 hypertensives with IMT < or =1 mm and 10 with IMT >1 mm.. CRP and TF and MCP-1 mRNA concentrations were significantly higher in IMT >1 mm hypertensives vs those with IMT < or =1 mm and controls. CRP had no effect on monocyte TF mRNA from either hypertensives or controls. CRP-stimulated monocytes from hypertensives, however, showed increased MCP-1 mRNA and protein expression compared with controls and LPS-stimulated cells.. Our findings suggest that the inflammatory response of blood monocytes plays an important role in the development of atherosclerosis and hypertension.

Topics: Adult; C-Reactive Protein; Carotid Arteries; Carotid Artery, Common; Carotid Artery, Internal; Carotid Stenosis; Cells, Cultured; Chemokine CCL2; Female; Humans; Hypertension; Lipopolysaccharides; Male; Monocytes; Thromboplastin; Tunica Intima; Tunica Media; Ultrasonography

Systemic hypertension is one of the main risk factors for atherothrombosis. Tissue factor (TF) is found in the adventitia of blood vessels and in the lipid core of atherosclerotic plaques, and is specifically expressed on monocyte or macrophage cell membrane surfaces. TF plays a pivotal role in blood clotting physiology and is involved in pro-inflammatory action and atherosclerotic plaque destabilization.. In this study we investigated whether there is any relationship between TF messenger RNA expression and activity in blood monocytes isolated from hypertensive patients with clinical signs of atherosclerosis, uncomplicated hypertensive individuals and normotensive control subjects.. Eighty subjects (41 men and 39 women, mean age 41 +/- 12 years) with untreated essential hypertension and 41 control subjects matched for sex and age were enrolled in the study. Patients were classified according to whether they had a normal ( 1 mm, 39 patients) intima-media thickness (IMT).. TF mRNA expression and activity in hypertensive individuals with no carotid atherosclerosis were no different from control subjects in unstimulated and stimulated monocytes. Abnormal IMT patients showed a higher TF mRNA expression compared with normal IMT hypertensive subjects (P < 0.001).. We demonstrated that TF mRNA and activity levels in monocytes obtained from uncomplicated hypertensive individuals are comparable with those of normotensive subjects, whereas atherosclerotic hypertensive patients showed increased levels of these parameters.

Topics: Adult; Atherosclerosis; Blood Pressure; Case-Control Studies; Female; Gene Expression; Humans; Hypertension; Lipopolysaccharides; Male; Middle Aged; Monocytes; Multivariate Analysis; Regression Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thromboplastin

Pulmonary hypertension is common in patients with chronic obstructive pulmonary disease (COPD), but the precise mechanism of vascular impairment in these patients is unknown. We, therefore, decided to investigate whether endothelial cell dysfunction is present in patients with COPD with a wide range of chronic airflow obstruction before the development of severe pulmonary hypertension. Selected plasma markers of endothelial cell activity were studied: nitrate+nitrite (NO-(2)/NO-(3)), thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), soluble selectins (endothelium sES, leukocyte sLS, platelet sPS), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1). Twenty-five patients with COPD (forced expiratory volume in one second/vital capacity [FEV(1)/VC] < 88% predicted) and 29 healthy control subjects were recruited to the study. Among patients nine had a pulmonary artery systolic pressure (PASP) between 15 and 30 mmHg, 13 between 32 and 38 mmHg, 2 had a PASP of 41 and 42 mmHg, respectively. One patient had severe pulmonary hypertension with a PASP of 70 mmHg. The average FEV(1) of patients with COPD was 46 +/- 4% predicted. As compared to control subjects, patients with COPD showed a significant increase in plasma levels of TM and TFPI, indicating that their endothelial cells are still able to produce potent coagulation inhibitors. Levels of NO-(2)/NO-(3) were similar in the two groups of subjects examined, further suggesting preserved endothelial function in patients with COPD. In regard to adhesion molecules, patients with COPD showed a reduction in sLS, sPS, and sPECAM-1, and an increase in sICAM-1. This study shows that endothelial cell activity is largely preserved in patients with COPD without severe pulmonary hypertension, suggesting that these patients, despite quite severe airway obstruction, retain reasonably normal endothelial function until they develop severe pulmonary hypertension.

Topics: Cell Adhesion; Endothelial Cells; Female; Humans; Hypertension; Male; Nitrates; Nitrites; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Solubility; Thrombomodulin; Thromboplastin

Topics: Adult; Aged; Arteriosclerosis; Factor VIIa; Female; Humans; Hypertension; Lipoproteins; Male; Middle Aged; Thromboplastin

Increasing evidence points toward a prothrombotic state in hypertension and atherosclerosis, conditions associated with thrombosis-related complications, such as myocardial infarction and stroke. We hypothesized that this increased risk of thrombogenesis may be related to endothelial damage/dysfunction and abnormal angiogenesis, and thus, an increased risk of future cardiovascular disease. Thrombogenesis, endothelial damage/dysfunction, and angiogenesis can be assessed by measurement of tissue factor (TF), von Willebrand Factor (vWF), flow-mediated dilatation (FMD), and vascular endothelial growth factor (VEGF), respectively. To test this hypothesis, we measured TF, vWF, FMD, and VEGF in 76 patients with systemic hypertension (71 men; mean age 64; mean blood pressure 167/72 mm Hg), considered additional risk factors such as diabetes, and related them to the patient's 10-year cardiovascular and cerebrovascular risk score using the Framingham equation. Patients were compared with 48 healthy normotensive controls. In these patients, the effects of 6 months of intensified blood pressure and (where appropriate) lipid-lowering treatment were investigated. In our patients, TF, VEGF, and vWF levels were higher, but FMD was lower (all p <0.001) compared with the controls. All markers correlated with each other and with both cardiovascular and cerebrovascular risk scores (all p <0.001). After intensified blood pressure and hypercholesterolemia treatment, total cholesterol, blood pressure, TF, VEGF, and vWF levels all decreased, whereas FMD increased (all p <0.001). Thus, in subjects with hypertension and other risk factors, endothelial damage/dysfunction (and thus, atherogenesis), thrombogenesis, and angiogenesis are abnormal, correlate with overall cardiovascular risk, and importantly, can be related to each other in a "Birmingham Vascular Triangle." Furthermore, these processes are beneficially affected by intensive blood pressure and lipid treatment.

Topics: Arteriosclerosis; Endothelial Growth Factors; Endothelium, Vascular; Female; Humans; Hypercholesterolemia; Hypertension; Intercellular Signaling Peptides and Proteins; Lymphokines; Male; Middle Aged; Neovascularization, Pathologic; Risk Factors; Thrombophilia; Thromboplastin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vasodilation; von Willebrand Factor

The rat model of chronic intoxication by N(G) -nitro-L-arginine methyl ester (L-NAME) induces severe systemic arterial hypertension and progressive ischemic lesions in the central nervous system and kidneys. We investigated the possible molecular basis of these thrombotic events.. Administration of L-NAME increased plasma markers of thrombin generation, thrombin-antithrombin complexes, and soluble glycoprotein V, measured by specific ELISA. Thrombin generation in vivo was associated with ex vivo platelet desensitization to adenosine 5'-diphosphate and collagen-induced aggregation. In the aortic layers and renal arterioles, tissue factor mRNA (semi-quantitative RT-PCR) and activity (coagulation assay) were increased. In contrast, tissue factor activity was not modified in glomeruli. In parallel, an impairment of the fibrinolytic system was demonstrated by an increase in plasma levels and arterial secretion of plasminogen activator inhibitor-1. In the arterial wall, plasminogen activator inhibtor-1 mRNA was significantly increased. Moreover, antifibrinolytic activity, studied by fibrin reverse zymography, was increased whereas all tissue-plasminogen activator activity secreted by the hypertensive arterial wall was detected as complexes with its specific inhibitor. In animals treated with the angiotensin-converting enzyme (ACE) inhibitor Zofenil, all of these parameters remained at control levels.. These results indicate that chronic blockade of nitric oxide production in rats results in enhancement of blood markers of thrombin generation associated with tissue factor induction and impairment of fibrinolysis in the vascular wall, which may contribute to the thrombotic complications associated with hypertension.

Topics: Animals; Anticoagulants; Arteries; Blood Platelets; Blood Pressure; Body Weight; Enzyme Inhibitors; Fibrinolytic Agents; Heart; Hemostasis; Hypertension; Kidney Glomerulus; Lipoproteins; Male; NG-Nitroarginine Methyl Ester; Organ Size; Plasminogen Activator Inhibitor 1; Platelet Activation; Random Allocation; Rats; Rats, Wistar; Thrombin; Thromboplastin; Tissue Plasminogen Activator

Clinical screening tests for blood coagulation that use plasma as samples cannot estimate the participation of platelets, leukocytes, and erythrocytes in blood coagulation system. We developed an assay to evaluate the total coagulation ability of blood and whole blood prothrombin time (WPT) using the principle of prothrombin time with the diluted-tissue factor as a trigger and a newly developed apparatus, STA, viscosity change detection system (electromagnetic clot detection). The activation of platelets by Ca ionophore shortened WPT and increased the expression of CD62P on the platelet surface. WPTs in citrated blood of spontaneous hypertensive rats (SHR) were significantly shorter than those of controls, Wistar Kyoto rats (WKY). Plasma levels of thrombin-antithrombin III (TAT) in SHR were significantly higher than those of WKY. Moreover, WPT and TAT levels were significantly correlated. Based on these results, WPT was found to be useful to estimate the activation of blood coagulation in whole blood.

Topics: Animals; Antithrombin III; Calcium; Evaluation Studies as Topic; Fibrinogen; Hypertension; Ionophores; Osmolar Concentration; Partial Thromboplastin Time; Peptide Hydrolases; Platelet Activation; Prothrombin Time; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sensitivity and Specificity; Thromboplastin

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Animals, Genetically Modified; Coronary Disease; Disease Models, Animal; Humans; Hypertension; Mice; Rats; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Thromboplastin; Thrombosis

Hemostasis factors may influence the pathophysiology of stroke. The role of brain hemostasis in ischemic hypertensive brain injury is not known. We studied ischemic injury in spontaneously hypertensive rats in relation to cerebrovascular fibrin deposition and activity of different hemostasis factors in brain microcirculation. In spontaneously hypertensive rats subjected to transient middle cerebral artery occlusion versus normotensive Wistar-Kyoto (W-K) rats, infarct and edema volumes were increased by 6.1-fold (P < 0.001) and 5.8-fold (P < 0.001), respectively, the cerebral blood flow (CBF) reduced during middle cerebral artery occlusion (MCAO) by 55% (P < 0.01), motor neurologic score increased by 6.9-fold (P < 0.01), and cerebrovascular fibrin deposition increased by 6.8-fold (P < 0.01). Under basal conditions, brain capillary protein C activation and tissue plasminogen activator activity were reduced in spontaneously hypertensive rats compared with Wistar-Kyoto rats by 11.8-fold (P < 0.001) and 5.1-fold (P < 0.001), respectively, and the plasminogen activator inhibitor-1 antigen and tissue factor activity were increased by 154-fold (P < 0.00001) and 74% (P < 0.01), respectively. We suggest that hypertension reduces antithrombotic mechanisms in brain microcirculation, which may enhance cerebrovascular fibrin deposition and microvascular obstructions during transient focal cerebral ischemia, which results in greater neuronal injury.

Topics: Animals; Blood Gas Analysis; Brain Ischemia; Capillaries; Cerebrovascular Circulation; Disease Models, Animal; Endothelium, Vascular; Fibrin; Fibrinolysis; Gene Expression; Hemostasis; Hypertension; Intracranial Thrombosis; Male; Microscopy, Electron; Neurologic Examination; Plasminogen Activator Inhibitor 1; Protein C; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Stroke; Thromboplastin

To investigate the changes of tissue factor (TF) and tissue factor pathway inhibitor(TFPI) activities in patients with hypertension or coronary atherosclerotic heart (CAH) disease.. TF activity was measured by two-stage assay, and TFPI activity was detected according to Sandset's method.. Plasma TF activity in both patients with hypertension and patients with CAH disease was higher than that of normal control(P < 0.05).. Hypercoagulative state may be involved in the pathogenetic processes of hypertension and CAH diseases. TF and TFPI activities have the likelihood to become the accessory diagnostic indexes for hypertension and CAH diseases.

Topics: Adult; Aged; Coronary Artery Disease; Female; Humans; Hypertension; Lipoproteins; Male; Middle Aged; Thromboplastin

We tested the hypothesis that enhanced intravascular coagulation in pregnancy could produce clinical symptoms similar to those of preeclampsia, such as hypertension, proteinuria, and edema. Having confirmed this, we then examined whether the pathological changes caused by intravascular coagulation could be suppressed by administration of antithrombin III (AT III), an endogenous inhibitor active to thrombin and factor X a. Intravascular coagulation was induced in Wistar rats on day 16-20 of pregnancy by 1-h arterial infusion of tissue thromboplastin (TP) through the left ventricle of the heart. One hour after the end of the infusion period, organ blood flows were measured by the radioactive ((57)Co-labeled) microsphere method, and fibrin deposition in organs was measured by radiolabeling with [(125)I] fibrinogen injected before TP infusion. Infusion of TP produced fibrin deposition in the kidney, lung, and liver, but not in the myometrium and placenta, as well as an 80% decrease in renal blood flow (RBF), with oliguria and proteinuria. TP also caused an increase in blood pressure (BP) accompanied by an increase in plasma renin activity (PRA), both of which were suppressed by bilateral nephrectomy before TP infusion. The prophylactic administration of AT III concentrates (60 or 300 U/kg intravenously (i.v.), followed by infusion of 30 or 150 U/kg/2 h, respectively) prevented all pathological changes in a dose-dependent manner. AT III increased placental blood flow regardless of the state of coagulation. These findings suggest that intravascular coagulation plays a significant part in the pathophysiology of preeclampsia and that AT III concentrates may have therapeutic potential in the treatment of this condition.

Topics: Animals; Antithrombin III; Blood Coagulation; Female; Fibrin; Hypertension; Kidney; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Proteinuria; Rats; Rats, Wistar; Regional Blood Flow; Renin; Serum Albumin; Thromboplastin

The amounts of tissue factor (TF) expressed by brain microvascular endothelial cells (BMECs) from normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were compared after stimulating the cells with different doses of lipopolysaccharide (LPS), thrombin, phorbol myristic acid (PMA), Ca(2+)-ionophore (A23187), or tumor necrosis factor (TNF) and interleukin-1 (IL-1). Treatment of cultured BMECs from WKY and SHR with all of these factors dose-dependently increased their total amount of TF; no substantive differences in the levels of enhanced TF expression were observed between WKY and SHR BMECs. We conclude that stimulated endothelium from rats with hypertension, a major stroke risk factor, is not hyperresponsive with respect to TF expression when compared to normotensive controls.

Topics: Animals; Brain; Calcimycin; Endothelium, Vascular; Hypertension; Interleukin-1; Lipopolysaccharides; Microcirculation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetradecanoylphorbol Acetate; Thrombin; Thromboplastin; Tumor Necrosis Factor-alpha

Topics: Adult; Factor VII; Female; Gestational Age; Heparin Cofactor II; Humans; Hypertension; Lipoproteins; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboplastin

The thromboplastin activity in blood monocytes was investigated in third-trimester pregnancies comprising 11 patients with severe pre-eclampsia, 10 with essential hypertension and 18 normal pregnancies. Thromboplastin activity in unstimulated monocytes from the severe pre-eclamptic group was on average three times that found in the normal pregnant group, but variation was wide and the differences were not statistically significant. Thromboplastin activity in endotoxin-stimulated monocytes was significantly higher in the severe pre-eclamptic group than in the other two groups (normal and chronic hypertensive). In the severe pre-eclamptic group, there was a significant negative linear correlation between thromboplastin activity of the endotoxin-stimulated monocytes and factor VII. Fibrinogen, factor VII and alpha 2-antiplasmin were significantly lower in the severe pre-eclamptic group than in the normal pregnant group, whereas no differences were observed in factors V, VIII, AT-III and prekallikrein.

Topics: Adult; Endotoxins; Factor V; Factor VII; Factor VIII; Female; Humans; Hypertension; Monocytes; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboplastin

1. Platelet factor 3, platelet survival, renal platelet localization and fibrinolytic activity have been studied in normotensive subjects with a previous history of pregnancy-associated hypertension. Studies were carried out up to 6 years after the complicated pregnancy. 2. Renal platelet localization was found to be significantly increased despite normal platelet survival and platelet factor 3 availability. Significant impairment of both resting and post-venous-occlusion fibrinolytic activity was also demonstrable. 3. The significance of these findings in relation to mediation of progressive intrarenal vascular disease is discussed.

Topics: Adult; Blood Platelets; Female; Fibrinolysis; Humans; Hypertension; Kidney; Lipids; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Complications, Hematologic; Thromboplastin

Topics: Animals; Arteries; Cerebrovascular Disorders; Fibrinolysis; Hypertension; Male; Plasminogen; Plasminogen Activators; Rats; Thromboplastin

The coagulation and fibrinolytic systems were investigated in a group of patients with essential hypertension during pregnancy, and the findings were compared with those of normal gravid women. Patients with essential hypertension exhibited the following significant differences: shortened partial thromboplastin times, thrombocytopenia, and decreased antithrombin III levels. Euglobulin lysis times and assays for fibrin breakdown products suggest that essential hypertension is not associated with changes in the fibrinolytic mechanism. Until more sophisticated studies can be performed on such patients, it cannot be concluded that the increased coagulability observed in pregnant patients with essential hypertension represents a state of intravascular coagulation.

Topics: Adolescent; Adult; Antithrombins; Blood Cell Count; Blood Coagulation; Blood Platelets; Female; Fibrinogen; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Serum Globulins; Thromboplastin

The clinical and laboratory features of a case of alphamethyldopa-induced thrombocytopenia are described. This is the second reported case in which the presence of alpha-methyldopa-induced platelet antibodies have been demonstrated.

Topics: Acute Kidney Injury; Antibody Formation; Aortic Aneurysm; Blood Coagulation Tests; Blood Platelets; Coombs Test; Female; Humans; Hypertension; Methyldopa; Middle Aged; Thrombocytopenia; Thromboplastin

Topics: Adolescent; Adult; Aged; Blood Coagulation; Female; Fibrinogen; Fibrinolysin; Fibrinolysis; Humans; Hypertension; Male; Middle Aged; Plasminogen; Thromboplastin

Topics: 5-Hydroxytryptophan; Abruptio Placentae; Animals; Blood Coagulation Factors; Desoxycorticosterone; Disease Models, Animal; Disseminated Intravascular Coagulation; Female; Fibrinogen; Fibrinolysis; Humans; Hypertension; Platelet Adhesiveness; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Hematologic; Pulmonary Circulation; Rabbits; Rats; Thrombocytopenia; Thromboplastin

Topics: Adult; Age Factors; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Disseminated Intravascular Coagulation; Factor V; Female; Fibrinogen; Fibrinolysin; Gestational Age; Humans; Hypertension; Parity; Plasminogen; Pre-Eclampsia; Pregnancy; Prothrombin Time; Thrombin; Thromboplastin

Topics: Adenosine Diphosphate; Adult; Antithrombins; Blood Cell Count; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Cold Temperature; Factor V; Factor VIII; Female; Fibrin; Fibrinogen; Fibrinolysis; Fibrinolytic Agents; Humans; Hypertension; Placenta; Placenta Diseases; Plasminogen; Platelet Adhesiveness; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboplastin

Topics: Animals; Arteries; Arteritis; Blood Coagulation; Blood Coagulation Tests; Blood Pressure Determination; Blood Sedimentation; Fibrinolysin; Hematocrit; Humans; Hypertension; Nephrectomy; Perinephritis; Polyarteritis Nodosa; Prothrombin Time; Rabbits; Research; Thrombin; Thromboplastin

Topics: Aged; Amputation, Surgical; Arteriosclerosis Obliterans; Blood Coagulation Disorders; Chronic Disease; Coumarins; Diabetes Mellitus; Follow-Up Studies; Humans; Hypercholesterolemia; Hypertension; Middle Aged; Myocardial Infarction; Thromboplastin

Topics: Animals; Arteriosclerosis; Blood Coagulation; Factor VII; Hemostasis; Hemostatics; Hypertension; Lipid Metabolism; Physiology; Rabbits; Research; Thromboplastin

Topics: Arteriosclerosis; Arteritis; Cholesterol; Humans; Hypercholesterolemia; Hypertension; Hypertension, Pulmonary; Lung; Pulmonary Artery; Thromboplastin; Thrombosis

Topics: Amniotic Fluid; Animals; Dogs; Factor XI Deficiency; Hypertension; Hypertension, Pulmonary; Thromboplastin