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PubMed2004

The angiotensin-converting-enzyme insertion/deletion polymorphism is not related to venous thrombosis.

The insertion/deletion (I/D) polymorphism of the gene for angiotensin-converting-enzyme (ACE) is associated with ACE plasma levels and activity. Conflicting results have been reported about the relevance of this polymorphism for venous thrombosis. The aim of the present study was to analyze the role of this polymorphism for deep venous thrombosis. The study was designed as a case-control study, including 330 patients with documented deep venous thrombosis and 354 controls. ACE genotype was determined by size-analysis of polymerase chain reaction products. Results showed that, ACE genotype frequencies were similar between patients (II: 24.8%; ID: 43.3%; DD: 31.8%) and controls (II: 22.9%; ID: 50.6%; DD: 26.6%, P = 0.15). The adjusted odds ratio of carriers of the DD geno-type for venous thrombosis was 1.24 (95% confidence interval 0.90-1.80). The polymorphism was furthermore not associated with age at first thromboembolic event or the occurrence of pulmonary embolism. From these results, we can conclude that the ACE I/D polymorphism is not a significant risk factor for deep venous thrombosis.

Adult↗

PubMed2004

Prevention of central venous line-related thrombosis by continuous infusion of low-dose unfractionated heparin, in patients with haemato-oncological disease. A randomized controlled trial.

We have conducted a prospective randomized controlled trial to evaluate the role of low-dose unfractionated heparin prophylaxis in preventing central venous line-related thrombosis in patients with haemato-oncological disease. Patients were randomly assigned to receive either prophylactic intravenous unfractionated heparin (continuous infusion of 100 IU/kg/daily) or 50 ml/daily of normal saline solution as a continuous infusion. CVLs were externalized, non tunneled, double lumen catheters. All CVLs were placed percutaneously by the same physician in the subclavian vein. Upper limb veins were systematically examined by ultrasonography just before, or <24 hours after, catheter removal, and in case of clinical signs of thrombosis. One hundred and twenty-eight CVLs were inserted. Catheter-related thrombosis occurred in 1.5% of the catheters inserted in patients of the heparin group, and in 12.6% in the control group (p = 0.03). No other risk factors were found for the development of catheter-related thrombosis. Two and three patients experienced severe bleeding in the heparin group, and in the control group, respectively (p = 0.18). There were no other side-effects clearly ascribable to the use of unfractionated heparin. This is the first prospective, randomized study, which shows that low-dose of unfractionated heparin is safe and effective to prevent catheter-related thrombosis in patients with haemato-oncological disease.

Adolescent↗

PubMed2005

High incidence of thrombosis in African-American and Latin-American patients with Paroxysmal Nocturnal Haemoglobinuria.

Paroxysmal Nocturnal Haemoglobinuria (PNH) results in a marked thrombophilic state by unknown mechanisms. Geographic differences in thrombosis incidence in PNH have been observed. We have reviewed 64 patients with "Classic PNH" from a single institution in order to determine the rate of thrombosis in different ethnic groups. When we compared African-Americans (n=11) and Latin-Americans (n=8) with other patients (n=45), we found that African-American and Latin-American patients are at increased risk [Hazard ratio 3.66 (p=0.005) and 3.52, (p=0.035) respectively by Cox regression]. Our data also suggest that this difference in the rate of thrombosis has an impact on length of survival. These findings demonstrate that ethnicity is a risk factor for thrombosis in PNH and have implications for decision-making regarding the management of these patients, including the prevention of thrombosis.

Adolescent↗

PubMed2005

Elevated plasma osteoprotegerin levels are associated with venous thrombosis and bleeding in patients with polycythemia vera.

Patients with polycythemia vera (PV) have an increased risk for the development of thrombohemorrhagic complications. The pathogenesis of these complications is still unclear. An important role in vascular disease has recently been attributed to osteoprotegerin (OPG). It has been shown that various tissues of the cardiovascular system produce OPG, and there is growing evidence of an association between elevated serum OPG levels and cardiovascular morbidity. We evaluated if OPG was associated with an increased risk of venous thrombosis or bleeding complications in a cohort of 114 PV patients. The analysis consisted of a retrospective and a prospective part. In the retrospective univariate analysis, a one unit change in OPG caused the odds of venous thrombosis to increase by 40% (p=0.005) and the odds of bleeding to increase by 52% (p=0.001). Multivariate analysis only slightly attenuated the association to 33% (p=0.03) and 37% (p=0.013) for venous thrombosis and bleeding, respectively. OPG was also related to the development of the combined outcome of venous thrombosis and bleeding in the prospective analysis (log-rank-test: p=0.017). This is the first report that links the occurrence of venous thrombosis or bleeding to elevated OPG levels.

Adult↗

PubMed2005

Angiotensin II enhances thrombosis development in renovascular hypertensive rats.

There is an increased number of in vitro evidence that angiotensin II (Ang II) may promote thrombosis. However there are no in vivo experiments exploring the effect of Ang II on thrombus formation. In the present study we have investigated the influence of Ang II on venous thrombosis in renovascular hypertensive rats. Furthermore, we examined the role of AT(1) receptor and Ang II metabolites: angiotensin III (Ang III) and angiotensin IV (Ang IV) in the mechanisms of Ang II action. The contribution of coagulation and fibrinolytic systems in the mode of Ang II action was also determined. Venous thrombosis was induced by ligation of vena cava. Ang II infused into rats developing venous thrombosis caused dose-dependent increase in thrombus weight, which was partially reversed by losartan, selective AT(1) antagonist. Ang III did not influence the thrombus formation in hypertensive rats, while Ang IV caused a marked increase in thrombus weight only in one of the used doses. Our study shows that Ang II via AT(1) receptor enhances thrombosis development. The prothrombotic effect of Ang II may partially depend on enhanced leukocytes adhesion to endothelial cells accompanied by accelerated fibrin formation and increased plasma level of PAI-1. Moreover, Ang II action is partially mediated by one of its metabolites - Ang IV.

Angiotensin II↗

PubMed2005

Bleeding and re-thrombosis in primary antiphospholipid syndrome on oral anticoagulation: an 8-year longitudinal comparison with mitral valve replacement and inherited thrombophilia.

The aim of this study was to compare bleeding and re-thrombosis in primary antiphospholipid syndrome (PAPS), mitral valve replacement (MVR) and inherited thrombophilia (IT) at different oral anticoagulation intensities. It entailed a prospective 8-year follow-up on 67 patients with PAPS, 89 with IT and 24 with MVR. Anticardiolipin (aCL) antibodies detected by Elisa and lupus anticoagulant by clotting assays. At INR 2-3 minor bleeding rate was higher in MVR (33.3) than PAPS (10.9) and IT (4.2)(p<0.0001). At INR 3-4 minor bleeding rate was higher in PAPS (142) than IT (33.3) and MVR (5.8)(p<0.0001). At either INR major bleeding rate were not significantly different across the three groups, but in PAPS major and minor bleeding rates were superior at INR 3-4 than INR 2-3 (p=0.02 and p<0.0001). Re-thrombosis rate was higher in PAPS than IT at INR 2-3 (4.0 vs 0.35) (p=0.01) and at INR 3-4 (10.5 vs. nil). The hazard ratio for re-thrombosis between PAPS and IT was 13 (95% IC 1.6-102.2, p=0.015). By regression analysis, baseline IgG aCL titre (>80 GPL) p=0.001) and male sex (p=0.03) independently predicted re-thrombosis. In conclusion, in PAPS, high intensity oral anticoagulation was not superior to conventional intensity in preventing re-thrombosis but was offset by greater bleeding rates. Male sex and elevated baseline IgG aCL predicted rethrombosis in PAPS that is 13-fold more re-thrombogenic than IT.

Adult↗

PubMed2004

Inhibition of endogenous leptin protects mice from arterial and venous thrombosis.

OBJECTIVE: Human obesity is associated with an increased risk for arterial and venous thrombosis and with elevated levels of leptin in the blood. Leptin administration promotes arterial thrombosis in mice, and leptin-deficient ob/ob mice have an attenuated thrombotic response to injury. Thus, endogenous leptin may regulate arterial and venous thrombosis in vivo. Experiments were performed to test this hypothesis. METHODS AND RESULTS: A leptin-neutralizing antibody was administered intravenously into wild-type mice 15 minutes before carotid artery injury with ferric chloride. The antibody-treated mice demonstrated prolonged times to thrombotic occlusion and formed unstable, embolizing thrombi. Thus, inhibiting leptin converted the thrombotic phenotype of wild-type mice into one that closely resembled that of ob/ob mice. The effect of leptin inhibition on venous thrombosis and pulmonary embolism was also investigated. Injection of a mixture of collagen and epinephrine into the jugular vein induced fatal pulmonary embolism in >90% of the control wild-type mice but in <40% of their antibody-treated counterparts. Histological analysis revealed that the antibody significantly reduced the number of occlusive thrombi in the pulmonary vessels. CONCLUSIONS: Inhibition of circulating leptin protects against arterial and venous thrombosis in mice and possibly in hyperleptinemic obese individuals.

Animals↗

PubMed2005

Importance of platelet phospholipase Cgamma2 signaling in arterial thrombosis as a function of lesion severity.

OBJECTIVE: Platelet activation occurs in response to adhesion receptors for von Willebrand factor (GPIb-V-IX) and collagen (GPVI and alpha2beta1 integrin) acting upstream of phospholipase C (PLC) gamma2. However, PLCbeta transduces signals from Galphaq protein-coupled receptors for soluble agonists (P2y1, TxA2/TP, and thrombin/PAR). A Gi-dependent pathway amplifies most of these responses. METHODS AND RESULTS: To evaluate the role of adhesion receptors signaling in arterial thrombosis, PLCgamma2 knockout mice were studied in blood perfusion assays over fibrillar collagen and in a laser-induced mesenteric artery model of thrombosis. In vitro, PLCgamma2-deficient platelets formed a single layer incapable of generating a thrombus on collagen, whereas Galphaq-deficient platelets formed reduced size aggregates compared with wild-type cells. In the in vivo model, PLCgamma2-/- mice displayed defective thrombus formation in superficial lesions but productive thrombosis after a more severe laser injury. In contrast, resistance to thrombosis was observed in Galphaq-/- mice in both levels of injury. CONCLUSIONS: These results demonstrate that signaling through PLCgamma2 plays an important role in arterial thrombosis, but that its contribution depends on the severity of the vascular lesion.

Animals↗

PubMed1992

Augmented arterial wall expression of type-1 plasminogen activator inhibitor induced by thrombosis.

Type-1 plasminogen activator inhibitor (PAI-1), the primary physiological inhibitor of endogenous plasminogen activators, modulates fibrinolysis, cell migration, and tissue repair. To determine whether genetic expression of PAI-1 is augmented in the walls of vessels exposed to thrombi but not to a direct physical insult such as electrical injury, we induced arterial thrombosis in rabbit carotid arteries with intraluminal surgical silk sutures and performed in situ hybridization for PAI-1 messenger RNA (mRNA) and immunohistochemistry for PAI-1 antigen at selected intervals. PAI-1 activity in plasma remained virtually constant. In contrast, PAI-1 mRNA increased in endothelial cells juxtaposed to thrombi, in smooth muscle cells adjacent to the neointima, and in macrophages surrounding the suture material. PAI-1 protein was detected in regions in which PAI-1 mRNA was expressed. The increased expression of PAI-1 mRNA colocalized with PAI-1 protein in the endothelium juxtaposed to thrombi may potentiate thrombosis by shifting the local balance between fibrinolysis and thrombosis toward thrombosis. Furthermore, it may alter vascular remodeling and predispose to stenosis after interventions such as angioplasty, in which local thrombosis cannot be avoided.

Animals↗

PubMed2000

Hyperlipidemia promotes thrombosis after injury to atherosclerotic vessels in apolipoprotein E-deficient mice.

The increased risk of hyperlipidemia on the development of complications of atherosclerosis is well established. Cholesterol-lowering therapies lead to a decrease in the incidence of vascular thrombotic events that is out of proportion to the reduction in plaque size. This suggests that the occurrence of acute thrombosis overlying a disrupted plaque is influenced by changes in lipid levels. The influence of acute hyperlipidemia on the development of thrombosis overlying an atherosclerotic plaque in vivo has not been extensively studied. We used a murine model of vascular injury induced by a photochemical reaction to elicit thrombus formation overlying an atherosclerotic plaque. Fifteen apolipoprotein E-deficient mice were maintained on normal chow until the age of 30 weeks. Five days before the induction of thrombosis, 6 mice were started on a high fat diet, and 9 mice were continued on normal chow. Mice then underwent photochemical injury to the common carotid artery immediately proximal to the carotid bifurcation, where an atherosclerotic plaque is consistently present. Mice maintained on normal chow developed occlusive thrombi, determined by cessation of blood flow, 44+/-5 minutes (mean+/-SEM) after photochemical injury, whereas mice fed a high fat chow developed occlusive thrombosis at 27+/-3 minutes (P<0.02). Histological analysis confirmed the presence of acute thrombus formation overlying an atherosclerotic plaque. These studies demonstrate a useful model for assessing the determinants of thrombosis in the setting of atherosclerosis and show that acute elevations in plasma cholesterol facilitate thrombus formation at sites of atherosclerosis after vascular injury.

Animals↗

PubMed2004

In vivo molecular imaging of acute and subacute thrombosis using a fibrin-binding magnetic resonance imaging contrast agent.

BACKGROUND: Plaque rupture with subsequent thrombosis is recognized as the underlying pathophysiology of most acute coronary syndromes and stroke. Thus, direct thrombus visualization may be beneficial for both diagnosis and guidance of therapy. We sought to test the feasibility of direct imaging of acute and subacute thrombosis using MRI together with a novel fibrin-binding gadolinium-labeled peptide, EP-1873, in an experimental animal model of plaque rupture and thrombosis. METHODS AND RESULTS: Fifteen male New Zealand White rabbits (weight, approximately 3.5 kg) were made atherosclerotic by feeding a high-cholesterol diet after endothelial aortic injury. Plaque rupture was then induced with the use of Russell's viper venom (RVV) and histamine. Subsequently, MRI of the subrenal aorta was performed before RVV, after RVV, and after EP-1873. Histology was performed on regions suggested by MRI to contain thrombus. Nine rabbits (60%) developed plaque rupture and thrombus, including 25 thrombi visually apparent on MRI as "hot spots" after injection of EP-1873. Histological correlation confirmed all 25 thrombi (100%), with no thrombi seen in the other regions of the aorta. In the remaining 6 rabbits (control) without plaque rupture, no thrombus was observed on the MR images or on histology. CONCLUSIONS: We demonstrate the feasibility of in vivo "molecular" MRI for the detection of acute and subacute thrombosis using a novel fibrin-binding MRI contrast agent in an animal model of atherosclerosis and acute/subacute thrombosis. Potential clinical applications include thrombus detection in acute coronary syndromes and stroke.

Acute Disease↗

PubMed2001

Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary gamma-radiation in patients with in-stent restenosis: Washington Radiation for In-Stent Restenosis Trial plus 6 months of clopidogrel (WRIST PLUS).

BACKGROUND: Intracoronary gamma-radiation reduces recurrent in-stent restenosis. Late thrombosis (>30 days after radiation therapy) is identified as a serious complication. The Washington Radiation for In-Stent Restenosis Trial (WRIST) PLUS, which involved 6 months of treatment with clopidogrel and aspirin, was designed to examine the efficacy and safety of prolonged antiplatelet therapy for the prevention of late thrombosis. METHODS AND RESULTS: A total of 120 consecutive patients with diffuse in-stent restenosis in native coronary arteries and vein grafts with lesions <80 mm underwent percutaneous coronary transluminal angioplasty, laser ablation, and/or rotational atherectomy. Additional stents were placed in 34 patients (28.3%). After the intervention, a closed-end lumen catheter was introduced into the artery, a ribbon with different trains of radioactive (192)Ir seeds was positioned to cover the treated site, and a dose of 14 Gy to 2 mm was prescribed. Patients were discharged with clopidogrel and aspirin for 6 months and followed angiographically and clinically. All patients but one tolerated the clopidogrel. The late occlusion and thrombosis rates were compared with the gamma-radiation-treated (n=125) and the placebo patients (n=126) from the WRIST and LONG WRIST studies (which involved only 1 month of antiplatelet therapy). At 6 months, the group receiving prolonged antiplatelet therapy had total occlusion and late thrombosis rates of 5.8% and 2.5%, respectively; these rates were lower than those in the active gamma-radiation group and similar to those in the placebo historical control group. CONCLUSIONS: Six months of clopidogrel and aspirin and a reduction in re-stenting for patients with in-stent restenosis treated with gamma-radiation is well tolerated and associated with a reduction in the late thrombosis rate compared with a similar cohort treated with only 1 month of clopidogrel and aspirin.

Aged↗

PubMed1980

Temporary transvenous pacing and femoral vein thrombosis.

The true incidence of thrombosis and pulmonary embolism in patients requiring temporary transvenous pacing via the femoral vein in unknown. Twenty-nine patients, mean age 66.2 years (range 38-79 years) who required temporary pacing were studied by bilateral contrast venography and perfusion lung scanning after removal of the pacing catheter. The patients were subdivided into two subgroups based on hemodynamic status. There was no statistical difference between the two groups with respect to mean age or the time the pacer catheter was in place and all patients were placed on low-dose heparin therapy. Ten patients (34%) had venographic evidence of thrombosis; six of them (60%) showed lung scan evidence of pulmonary emboli. The hemodynamically compromised group consisted of seven patients, six (85%) of whom had thrombosis; three of these six (50%) had pulmonary emboli. Of the 22 patients in the hemodynamically stable group, four (18%) had thrombosis and two of these (50%) had pulmonary emboli. Venous thrombosis, with subsequent pulmonary emboli, is a serious complication of temporary transvenous pacing using the femoral approach, despite the use of prophylactic low-dose heparin.

Adult↗

PubMed1994

Local delivery of an antithrombin inhibits platelet-dependent thrombosis.

BACKGROUND: Platelet-dependent thrombosis can be effectively inhibited by intravenous administration of direct thrombin antagonists. However, an increased propensity for abnormal bleeding has been associated with systemic administration of these agents. The goal of this study was to determine whether local delivery of a potent thrombin inhibitor, D-Phe-L-Pro-L-Arg chloromethyl ketone (PPACK), could inhibit platelet-dependent thrombosis without altering systemic hemostatic function. METHODS AND RESULTS: Thrombus formation was measured by quantitative imaging of 111In-labeled platelet deposition on segments of thrombogenic vascular graft interposed in arteriovenous shunts in a porcine model. Intravenous administration of PPACK inhibited platelet deposition at a dose of 12.5 micrograms/kg per minute, which was associated with significant prolongations of both template bleeding times and activated partial thromboplastin times. By contrast, local infusion of PPACK at a dose of 0.02 micrograms/kg per minute (ie, a 600-fold smaller dose) into the fluid boundary layer at the interface between flowing blood and the thrombogenic segment produced equivalent inhibition of platelet deposition without prolonging either the bleeding time or the activated partial thromboplastin time. In addition, static exposure of a mural thrombus to solutions of PPACK at concentrations > or = 2.5 mg/mL for 15 minutes produced sustained inhibition of platelet-dependent thrombosis with no change in hemostatic measurements. CONCLUSIONS: These results indicate that local delivery of the direct antithrombin PPACK, by either boundary layer infusion or static application techniques, effectively inhibits platelet-dependent thrombosis at doses that are several orders of magnitude less than the systemic dose required for an equivalent antithrombotic effect. In contrast to the systemic administration of PPACK, local delivery produced maximal inhibition of thrombosis without alterations in hemostasis.

Amino Acid Chloromethyl Ketones↗

PubMed1994

Sudden death in the young. Is acute coronary thrombosis the major precipitating factor?

BACKGROUND: Atherosclerotic coronary artery disease, complicated by acute thrombosis, is the usual cause of sudden death in adults. This study addresses the pathology of coronary arteries in sudden death in the young (< or = 35 years old). METHODS AND RESULTS: Among 200 consecutive cases of sudden death in youth in the Veneto region of Italy, 37 (33 men and 4 women, age 18 to 35 years; mean, 29.4 years) showed obstructive atherosclerotic coronary artery disease in the absence of other cardiac pathological conditions and causes of death. No patient had previous angina pectoris or myocardial infarction. Cardiac arrest occurred at rest in 30 subjects and was related to effort in 7. A histological study was carried out on the obstructive coronary plaques. Degree of lumen stenosis and extension of lipid core and intimal fibrocellular hyperplasia facing the lumen were calculated morphometrically. Immunohistochemistry and electron microscopy were used to further characterize the plaque cell population. Single-vessel disease was found in 33 patients and triple-vessel disease in 4, with an overall total of 45 obstructive plaques, 34 of which were located in the proximal left anterior descending coronary artery. At histological study, only 10 plaques from 10 patients showed acute thrombosis (occlusive in 5 and subocclusive in 5); the remaining 35 were uncomplicated. Thirty-one plaques were fibrous in nature, while the other 14 were atheromatous. Compared with the atheromatous lesions, the fibrous plaques were rarely complicated by thrombosis (3% versus 64%; P < .001) and distinctly exhibited a fairly well-preserved tunica media (81% versus 21%; P < .001) as well as a stratum of neointimal fibrocellular hyperplasia (68% versus 7%; P < .001), which on immunohistochemistry and electron microscopy appeared to be proliferating smooth muscle cells. CONCLUSIONS: In our study population, sudden death was precipitated by acute coronary thrombosis in only 27% of patients with obstructive coronary atherosclerotic plaque. Most of the young victims of sudden death with obstructive coronary atherosclerosis showed single-vessel disease that affected the left anterior descending coronary artery and was due to fibrous plaques with neointimal smooth muscle cell hyperplasia and a preserved tunica media in the absence of acute thrombosis.

Acute Disease↗

PubMed1995

Endovascular stent design dictates experimental restenosis and thrombosis.

BACKGROUND: Vascular interventions that maximize initial lumen diameter provoke extensive neointimal hyperplasia but minimize its effects, causing long-term lumen size to be greater. Nevertheless, interventions such as endovascular stents, which increase lumen size above that achieved with balloon angioplasty, are subject to frequent thrombosis and restenosis. It has been unclear whether the response to stent-induced injury is determined solely by the degree of stent-induced arterial expansion or whether the geometric configuration of the stent or the material left in contact with the vessel wall also contribute. METHODS AND RESULTS: We examined the vascular response to steel stents deployed in denuded rabbit iliac arteries for 14 days. In one set of experiments, the effects of sten configuration were examined, holding diameter, mass, surface area, and stent surface material constant. In another set, stent surface material was changed, with mass, configuration, and diameter unaltered. Changing stent configuration to reduce strut-strut intersections by 29% without affecting mass or surface area reduced vascular injury by 42%, thrombosis by 69%, and neointimal hyperplasia by 38%. Monocyte adhesion to stented arteries correlated linearly with vascular trauma and neointimal hyperplasia (r = .96, P < .01 for each). When the stainless steel surface was coated with an inert polymer material, vascular injury and neointimal hyperplasia were unchanged but thrombosis was eliminated. CONCLUSIONS: Surface material and geometric configuration of stents may be more important than postplacement diameter in determining neointimal hyperplasia and thrombosis. Alterations in configuration affect vascular injury and neointimal hyperplasia, while surface material plays a greater role in thrombosis. Monocytes may be important modulators of stent-induced intimal thickening. Clinical confirmation of these findings may alter coronary stent deployment techniques and future stent designs.

Animals↗

PubMed1997

Human platelet Ca2+ mobilization, glycoprotein IIb/IIIa activation, and experimental coronary thrombosis in vivo in dogs are all inhibited by the inotropic agent amrinone.

BACKGROUND: Inotropic drugs are often used to treat acute, severe heart failure resulting from acute myocardial infarction and other unstable coronary artery syndromes. However, catecholamine inotropic agents may potentiate coronary thrombosis via a platelet alpha2-adrenergic mechanism, thus exacerbating the original problem. The present studies were designed to determine whether the nonadrenergic inotropic and vasodilator drug amrinone, which elevates platelet cAMP levels, would both inhibit human platelet Ca2+ mobilization and adhesion molecule expression ex vivo and protect against experimental coronary thrombosis in vivo in dogs. METHODS AND RESULTS: Human platelets in suspension were preincubated with amrinone 2.5 to 15 microg/mL; stimulated with the agonists thrombin 0.1 U/mL, ADP 10(-6) mol/L, or arginine vasopressin 10(7) mol/L; and studied for Ca2+ mobilization, glycoprotein IIb/IIIa activation, and P-selectin expression by fluorescent flow cytometry methods. Experimental coronary thrombosis in vivo was studied in an open-chest dog model with critical coronary artery stenosis and deep vessel wall injury. Results showed that at the cellular level, amrinone inhibited agonist-induced Ca2+ mobilization and had modest inhibitory effects on adhesion molecule expression. In vivo in dogs, intravenous amrinone 2 mg/kg plus infusion at 20 microg x kg(1) x min(-1) completely abolished coronary thrombosis. CONCLUSIONS: The fact that amrinone inhibited human platelet activation at the cellular level and protected against experimental coronary thrombosis in vivo in dogs suggests a potentially advantageous antithrombotic action for this inotropic and vasodilator drug.

Amrinone↗

PubMed1999

G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men.

BACKGROUND: A single base pair mutation in the prothrombin gene has recently been identified that is associated with increased prothrombin levels. Whether this mutation increases the risks of arterial and venous thrombosis among healthy individuals is controversial. METHODS AND RESULTS: In a prospective cohort of 14 916 men, we determined the prevalence of the G20210A prothrombin gene variant in 833 men who subsequently developed myocardial infarction, stroke, or venous thrombosis (cases) and in 1774 age- and smoking status-matched men who remained free of thrombosis during a 10-year follow-up (control subjects). Gene sequencing was used to confirm mutation status in a subgroup of participants. Overall, carrier rates for the G20210A mutation were similar among case and control subjects; the relative risk of developing any thrombotic event in association with the 20210A allele was 1.05 (95% CI, 0.7 to 1.6; P=0.8). We observed no evidence of association between mutation and myocardial infarction (RR=0.8, P=0.4) or stroke (RR=1.1, P=0.8). For venous thrombosis, a modest nonsignificant increase in risk was observed (RR=1.7, P=0.08) that was smaller in magnitude than that associated with factor V Leiden (RR=3.0, P<0. 001). Nine individuals carried both the prothrombin mutation and factor V Leiden (5 controls and 4 cases). One individual, a control subject, was homozygous for the prothrombin mutation. CONCLUSIONS: In a large cohort of US men, the G20210A prothrombin gene variant was not associated with increased risk of myocardial infarction or stroke. For venous thrombosis, risk estimates associated with the G20210A mutation were smaller in magnitude than risk estimates associated with factor V Leiden.

Adult↗