bluuebunny/crossref_metadata_2025 huggingface dataset:
Dedifferentiated Chondrosarcoma
Authors: Elmberger P.G. , Bridge J.A. , Noel S.M. , Neff J.R. , Walker C.W. , Johansson S.L.
Published: November 2007

We describe the clinicopathologic and cytogenetic findings of an unusual dedifferentiated chondrosarcoma with a rhabdomyosarcomatous component in a case report and review the relevance of these findings with respect to seven previously reported cases. Cytogenetic studies of dedifferentiated chondrosarcoma are limited to 2 previously described cases, both with dedifferentiated components distinct from this case. In this study, cytogenetic analysis of 3 separate specimens, biopsy with chondrosarcoma, definitive surgical, and lung metastasis with rhabdomyosarcomatous component, revealed clonal karyotypic aberrations in each. A structural abnormality involving the short arm of chromosome 17 and extra copies of chromosomes 5, 7, 12, and 20 were common to all three specimens. These findings reveal multiple shared chromosomal anomalies between the primary chondrosarcoma and the dedifferentiated components, which suggests a clonal evolution. Int J Surg Pathol 2(4):319-328, 1995
Investigative Concerns in Demonstrating Reduced Risk from Reversing Left Ventricular Hypertrophy
Authors: Frohlich Edward D. , Aristizabal Dagnovar , Soria Federico , Messerli Franz H.
Published: November 2007

Background: To demonstrate reduced risk from reversing left ventricular hypertrophy (LVH) in hypertension, one must show that it is independent of blood pressure reduction.

Methods and Results: A feasibility study was conducted with 15 patients. The study employed 48-hour Holter recording, exercise treadmill (for ST-segment changes) and, as nec essary, thallium scintigraphy and coronary angiography. All patients were treated for 3 months with quinapril (10 mg) and demonstrated decreased mean arterial pressure (125 ± 3.1 vs 103 ± 1.9 mmHg; P < .01) and left ventricular mass index (125 ± 6.4 vs 104 ± 4.9; P < .02) with preserved left ventricular function. There were no significant changes in these patients with moderate LVH in the incidence of arrhythmias; however, 4 of the 15 patients developed ST-segment changes prior to LVH reversal, and these changes did not recur in 3 patients following reversal of LVH or when pressure was allowed to rise.

Conclusions: Ischemic changes, rather than development of arrhythmias, may be of greater value in demonstrating risk reduction with LVH reversal. Nloreover, these preliminary data suggest pitfalls in demonstrating risk reduction after LVH reversal, indicating that more sen sitive and adequate techniques are necessary to show risk reduction from LVH.
Protective Effect of Elastase Inhibition Against Myocardial Dysfunction and Injury Induced by Ischemia and Reperfusion in Isolated Rat Hearts
Authors: Yang B.C. , Williams J.C. , Mehta J.L.
Published: November 2007

Background: Elastase release has been incriminated in the genesis of reperfusion-induced myocardial dysfunction and injury, and elastase inhibitors have been reported to reduce myocardial dysfunction in dogs subjected to coronary artery occlusion and reperfusion.

Methods and Results: To examine if efastase inhibition will modify myocardial dysfunction and injury induced by ischemia and reperfusion in isolated hearts, hearts from male Sprague Dawley rats were subjected to 30 minutes of total ischemia followed by 30 minutes of reper fusion. Ischemia-reperfusion resulted in myocardial dysfunction (increase in coronary perfu sion pressure and decrease in myocardial contraction), injury (measured as creatine kinase release), and lipid peroxidation (myocardial malondialdehyde). Perfusion of hearts with an elastase inhibitor, ICI200,880, protected against myocardial dysfunction, injury and lipid per oxidation following ischcmia-reperfusion. As expected, perfusion with superoxide dismutase protected the hearts against hemodynamic deterioration following ischemia-reperfusion. In in vitro studies, there was no direct effect of ICI200,880 on superoxide anion generation.

Conclusions: ICI200,880 seems to exert cardioprotective effects against ischemia-reperfu sion-induced injury and myocurdial dysfunction in isolated buffer-perfused hearts, most likely by an elastase-like protease inhibitory activity.
Reduction of Myocardial Infarct Size in the Rabbit by a Carbohydrate Analog of Sialyl Lewisx
Authors: Kilgore Kenneth S. , Park James L. , Chi Liguo , Musser John H. , Date Vandana , Abbas Saeed , Lucchesi Benedict R.
Published: November 2007

Background: Available data suggest that the accumulation of neutrophils within the myocardium following an ischemic event plays an important role in the pathogenesis of myocardial ischemia/reperfusion injury. It is of interest, therefore, to develop pharmacologic agents designed to inhibit neutrophil adhesion to the endothelium.

Methods and Results: A synthetic carbohydrate analog to the P-selectin ligand sialyl Lewis x (sLex) was evaluated for its ability to protect the myocardium from ischemia/reperfusion injury. Open chest anesthetized rabbits were subjected to 30 minutes occlusion of the left cir cumflex artery followed by 5 hours of reperfusion. Vehicle or sLe x analog (10 mg/kg) was administered intravenously before the onset of reperfusion and every hour during the reper fusion period. Myocardial infarct size in rabbits treated with the sLex analog was significantly reduced when compared to rabbits treated with vehicle (28 ± 9% vs 57 ± 10% of the area at risk, P < .05). The compound did not alter circulating neutrophil counts or myocardial oxy gen demand as determined by the rate-pressure product. Furthermore, neutrophil accumula tion within the ischemic region was decreased by 44% (P < .05) in the hearts of animals receiving sLex analog as compared to vehicle.

Conclusions: Carbohydrate derivatives of sLex may be effective in reducing the degree of myocardial injury after ischemia/reperfusion.
The Novel Class III Antiarrhythmic Agent MS-551 Blocks the Cardiac Inward Rectifier With Greater Potency Than Sotalol or E-4031: Possible Relevance to Reverse Use Dependence
Authors: Nakaya Yutaka , Martin Donald K. , Campbell Terence J.
Published: November 2007

Background: The tendency for the electrophysiologic effect of class III antiarrhythmic agents (action potential prolongation) to be diminished at faster heart rates represents a major drawback of this class of drug and is usually referred to as "reverse use dependence." A novel class III agent, MS-551, has recently been reported to exhibit less reverse use dependence than E-4031. We set out to investigate whether this observation may be due to differential blockade of the inward rectifier current (iK1) by these drugs.

Methods and Results: We recorded iK1 using single channel methods and cell attached patch configurations, with standard patch clamp technology. Neither E-4031 nor racemic sotalol in concentrations up to 100 μM had any significant effect on the open probability or kinetics of iK1 channels. MS-551 produced a concentration-dependent reduction in the open probability of i K1 without altering the single-channel conductance. Openings to subconductance levels were abolished in three of six patches in which they had been frequently present in the absence of drug. MS-551 had no effect on mean channel open time but increased the slower component of the closed time.

Conclusions: MS-551, unlike E-4031 and sotalol, appears to produce significant blockade of the inwardly rectifying potassium channel at clinically relevant concentrations. We propose that this might provide a partial explanation for the observed differences in their response to rate changes.
Mibefradil: A New Selective T-Channel Calcium Antagonist for Hypertension and Angina Pectoris
Authors: Frishman William H.
Published: November 2007

Calcium antagonists are an established therapy for patients with hypertension and angina pectoris, but their current usage is often limited by their pharmacologic profiles and side effects. Mibefradil is a recently developed calcium antagonist with a unique chemical struc ture, site of action, and set of pharmacologic effects. Unlike currently available calcium antagonists, which block only L-type calcium channels, mibefradil selectively blocks T-type channels as well as L-type channels. It is further distinguished from other calcium antago nists in that it is the first member of a new class of calcium antagonists, the tetralol deriva tives. With chronic oral dosing, mibefradil attains steady-state plasma concentrations within 3-4 days, has a bioavailability of approximately 90%, and a plasma half-life of 17-25 hours. It has a gradual onset of action and can be administered once daily without regard to food intake. It increases coronary blood flow and lowers peripheral vascular resistance. The vasodilatory effects of mibefradil are associated with a lack of inotropic effect on myocardium, lack of neurohormonal activation, and a reduction in heart rate. In clinical trials it has been demonstrated to be an effective agent in the treatment of patients with hyperten sion and angina pectoris, with a good safety and tolerability profile regardless of age, gender, or race.
Antihypertensive Therapy in Patients Undergoing Noncardiac Surgery
Authors: DeQuattro Vincent , Li Deping
Published: November 2007

Thirty-one million patients in the United States undergo surgical procedures every year. Approximately 10%—the majority of these with hypertension—are at an increased risk for perioperative and postoperative cardiovascular morbidity and mortality. Thus, hypertensive patients requiring surgery, especially the 2.1 million undergoing noncar diac procedures, should be evaluated carefully for the magnitude, and if severe, the cause of the hypertension. Additionally, their associated metabolic and cardiovascular status should be characterized and corrected with aggressive therapy. Hypertensive patients with known ischemic heart disease, those with multiple risk factors for ischemic heart disease (IHD), some with valvular heart disease, and those with congestive heart failure should be evaluated for their ability to perform the physical and social activities of everyday life, and, when nec cssary, have formal stress testing. Most studies suggest that blood pressures of 180/110 mm Hg or greater are associated with a greater risk for perioperative ischemic events. Therefore, the goals of blood pressure control should be to reduce the blood pressure without jeopardiz ing organ function. Antihypertensive medication should be administered until the time of surgery. β-Reccptor blockers should be instituted or continued in patients with angina and in some patients with congestive heart failure. Those without prior antihypertensive therapy might be best treated with β-blocker therapy perloperatively as evidenced by the Multicenter Study of Perioperative Research Group with atcnolol and those earlier studies with metopro lol. The risks of the surgery should be discussed with the patient so the risks can be weighed against the expected benefit. Studies suggest that perioperative risk for any patient, and espe cially patients with hypertension, are in part related to the adrenergic arousal before, during, and after the procedure as evidenced by the rise in heart rate and blood pressure, along with the liberation of clotting factors and increased risk for plaque rupture, coronary vasoplasm, and consequent myocardial infarction and fibrosis.
Protective Effects of Iganidipine on Morphological and Functional Changes of Arteries in Hypertensive Dahl Rats
Authors: Shirahase Hiroaki , Uehara Yoshio , Kanda Mamoru , Wada Katsuo , Ichikawa Atsuko , Kobayashi Yoshihiko , Funahashi Norio
Published: November 2007

Background: This study was performed to examine the protective effects of iganidipine, a new water-soluble calcium antagonist, on the morphological and functional changes of arteries in Dahl salt-sensitive (Dahl-S) rats.

Methods and Results: Vehicle and iganidipine were administered orally to Dahl-S rats fed a high-salt diet (HSD) for 8 weeks. Aorta, superior mesenteric arteries (SMA), and peri pheral mesenteric arteries (PMA) were examined light-microscopically or electron- microscopically. Relaxant responses of isolated aorta and SMA were recorded isometrically. In rats fed HSD, blood pressure was markedly increased. Light microscopy showed intimal and medial hypertrophy, periarteritis, and narrowed arterial lumen in the PMA. Transmis sion and scanning electron microscopy or light microscopy showed medical thickness in the aorta and SMA and hypertrophy of endothelial cells and dilatation of the subendothelial space only in the aorta. In the SMA, both endothelium-dependent relaxation (EDR) and endothelium-independent relaxations (EIR) were reduced to a similar extent. In the aorta, the EDR was more markedly attenuated than the EIR. Iganidipine at 3 mg/kg/day showed a 24-h sustained hypotensive effect and completely prevented the morphological and func tional changes in both arteries. Iganidipine at 1 mg/kg/day, which lowered blood pressure only for several hours, decreased the injuries in PMA and aortic endothelium and moder ately restored the EDR in the aorta. Iganidipine at 0.3 mg/kg/day had no effects.

Conclusions: In Dahl-S rats fed an HSD, iganidipine completely prevented all the changes at a sustained-hypotensive dose and prevented the injuries of PMA and aortic endothelium and the reduction of EDR in the aorta at a nonsustained hypotensive dose. Nonhemody namic effects of iganidipine may be partly involved in its protective effects against arterial injuries.
Angiotensin-Converting Enzyme Inhibition Delays Onset of Glucosuria With Regression of Renal Injuries in Genetic Rat Model of Non-Insulin-Dependent Diabetes Mellitus
Authors: Uehara Yoshio , Hirawa Nobuhito , Numabe Atsushi , Kawabata Yukari , Nagoshi Hiroshi , Negoro Hideyuki , Fujiwara Satoshi , Gomi Tomoko , Ikeda Toshio , Goto Atsuo , Omata Masao
Published: November 2007

Background: The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non-insulin-dependent diabetes mellitus (NIDDM). We investigated whether angiotensin inhibition influences the onset of NIDDM and brings about a regression of renal injury in diabetes mellitus.

Methods and Results: Six-week-old OLETF rats were treated with the angiotensin-con verting enzyme (ACE) inhibitors imidapril or enalapril for 16 weeks. Systolic blood pres sure is increased in an age-dependent manner in OLETF rats. In this study, the elevation in systolic blood pressure was dose-dependently reduced by ACE inhibitor treatment. In OLETF rats, plasma concentrations of insulin and glucose increased and the glucosuria occurred at the age of 22 weeks. Simultaneously, OLETF rats exhibited proteinuria and nodular lesions in glomeruli. The ACE inhibitor treatment almost completely reduced glu cosuria, and also decreased plasma concentrations of insulin and glucose in OLETF rats. ACE inhibitor treatment lessened the proteinuria and attenuated morphologically the severity of nodular lesions in OLETF rats. Moreover, increases in plasminogen activator inhibitor 1 (PAI-1) in OLETF rats were reduced by the ACE inhibitor treatment, and the improvement of glomerular lesions was related to decreases of PAI-1 and angiotensin II levels in plasma but not to improvement of glucose metabolism.

Conclusions: ACE inhibitors delay onset of NIDDM with attenuation of kidney injury. The regression of kidney lesions is probably due to angiotensin reduction but not to glucose metabolism per se. ACE inhibitor drug therapy may be useful in preventing NIDDM and the subsequent renal injury in patients with NIDDM.
Age-Dependent Changes in the Effects of Amiodarone on Rabbit Cardiac Myocyte Contractions
Authors: Fuhua Chen  , Naim Suhaila , Friedman William F. , Klitzner Thomas S. , Wetzel Glenn T.
Published: November 2007

Background: Intravenous amiodarone has increasingly been used to control life-threaten ing atrial and ventricular arrhythmias. In addition to its four antiarrhythmic properties, amio darone may have complex effects on intracellular Ca 2+ stores and myocyte contractility.

Methods and Results: Contraction amplitude was recorded for cardiac ventricular myo cytes isolated from neonatal and adult rabbits. Sarcoplasmic reticulum (SR) Ca2+ stores were loaded to steady-state levels by a train of eight electric field stimulations. The SR Ca2+ load was quantified by recording the contraction amplitude resulting from the complete depletion of SR Ca2+ stores by exposing the cell to a 1-second pulse of 10 mmol/L caffeine. After the cells were exposed to 1 μmol/L amiodarone for 10 minutes, electrically stimulated contraction amplitudes significantly decreased in both adult and neonatal cells. Caffeine- induced cell contraction amplitudes were not affected by amiodarone in adult ventricular myocytes. By contrast, amiodarone markedly inhibited caffeine-induced contractions in neonatal ventricular myocytes. The inhibitory effect of amiodarone on the caffeine-induced contractions was not replicated by Ca2+ channel blockade with diltiazem.

Conclusions: Amiodarone markedly inhibits caffeine-induced contraction in neonatal myo cytes but has no significant effect on adult myocytes. Ca2+ influx through amiodarone-sensitive Ca2+ channels may play a primary role in maintaining SR Ca2+ stores in neonatal heart.
Mechanisms of Hydrogen Peroxide—Induced Increase in Intracellular Calcium in Cardiomyocytes
Authors: Xi Wang  , Takeda Satoshi , Mochizuki Seibu , Jindal Rashi , Dhalla Naranjan S.
Published: November 2007

Background: Hydrogen peroxide (H2O2) in high concentrations has been implicated in heart dysfunction attributable to ischemia-reperfusion. Although H 2O2 is also known to increase the intracellular concentration of Ca2+ ([Ca2+]i) in cardiomyocytes, the mecha nisms for such a change are not clear. In this study, the sources and mechanisms of increase in [Ca 2+]i caused by high concentrations of H2O 2 in cardiomyocytes were explored.

Methods and Results: Cardiomyocytes were isolated from adult male Sprague-Dawley rats. Cell viability was examined by trypan blue exclusion test. [Ca2+] i was measured by employ ing cell suspension at room temperature and Fura-2 fluorescence technique. Incubation of cells with 0.25-1 mmol/L H2O2 increased [Ca 2+]i in a time- and concentration-dependent manner. Catalase attenuated the H2O2-induced increase in [Ca2+] i significantly, whereas mannitol showed no effect. Neither the presence of verapamil, a sarcolemmal Ca2+ channel blocker, nor the removal of Ca2+ from the medium produced any significant reduction in the H2O2-induced increase in [Ca2+] i. Conversely, treatment of cardiomyoctes with stauro sporin, a protein kinase C inhibitor, thapsigargin, a sarcoplasmic reticulum Ca2+-pump aden osine triphosphatase inhibitor, as well as ryanodine, a sarcoplasmic reticulum Ca2+-release channel blocker, markedly prevented the 0.5-mmol/L H2O2-induced increase in [Ca 2+]i. The responses of cardiomyoctes to H2O 2 and other Ca2+-mobilizing agents, such as KCl or aden osine triphosphate, were additive. No changes in cardiomyocyte viability were seen on incu bation with 0.5 and 1 mmol/L H2O2. Perfusion of the isolated heart with H2O2 (0.1-0.5 mmol/L) depressed the left ventricular developed pressure, rate of contraction, and rate of relaxation, whereas the left ventricular end-diastolic pressure was increased.

Conclusions: These results indicate that formation of H2O2 under pathophysiological con ditions such as ischemic heart disease may induce changes in Ca2+ homeostasis in cardiomy ocytes and may induce contractile dysfunction. Furthermore, the sarcoplasmic reticulum involving a protein kinase C-mediated mechanism appears to be the main site of action of H 2O2 in cardiomyocytes.
Domoic Acid Attenuates the Adenosonine-5'- Triphosphate-Induced Increase in [Ca2+] i in Adult Cardiomyocytes
Authors: Nijjar Mohinder S. , Pierce Grant N. , Nijjar Satnam S. , Dhalla Naranjan S.
Published: November 2007

Background: Although domoic acid (DA), a shellfish neurotoxin, carries a negative surface charge at physiological pH like that of adenosine-5'-triphosphate (ATP), very little is known about its cellular effects. In view of the potentially significant role of extracellular ATP as a signaling molecule for increasing the intracellular concentration of Ca2+ ([Ca2+]i), we examined the possibility that DA may interfere with this signal transduction mechanism in the myocardium.

Methods and Results: Cardiomyocytes were isolated from rat heart and loaded with Fura-2 to measure the [Ca2+]i. ATP produced a gradual rise in [Ca2+]i, reaching a peak level in 25- 30 seconds and declining thereafter. DA did not affect the [Ca2+]i in cardiomyocytes; however, it diminished the ATP-induced elevation in [Ca2+]i in a concentration-dependent manner. Kainic acid, an analogue of DA, had a similar effect but at a 25-fold higher concentration, whereas glutamate and aspartate did not modify the action of ATP. Well-known inhibitors of L-type voltage-sensitive Ca2+ channels, nifedipine and nicardipine, depressed the ATP- induced increase in [Ca2+ ]i, but DA did not produce additive effects with either of these agents. On the other hand, DA potentiated the KCl-induced increase in [Ca2+]i in quiescent cardiomyocytes and augmented the nicardipine-sensitive Ca2+ transients in electrically stimulated cardiomyocytes.

Conclusions: These results suggest that DA may diminish the ATP-induced increase in [Ca 2+]i by inhibiting the ATP interaction with cardiomyocytes in a specific manner.
Nifedipine and Bay K 8644 Induce an Increase of [Ca2+] i and Nitric Oxide in Endothelial Cells
Authors: Berkels Reinhard , Mueller Andreas , Roesen Renate , Klaus Wolfgang
Published: November 2007

Background: The dihydropyridine-induced vasorelaxation is partly dependent on the endothelium, which does not express L-type calcium channels. Because nitric oxide (NO) is one of the most important endothelium-derived vasorelaxing factors, we investigated how the calcium antagonist nifedipine and the calcium agonist Bay K 8644 modulate intracellu lar calcium and NO formation in porcine endothelial cells.

Methods and Results: NO formation of porcine aortic endothelial cell cultures and of native endothelium of intact porcine coronary arteries was measured with an electrochemi cal electrode, and the intracellular concentration of Ca2+[Ca2+]iwas evaluated using the Fura-2 technique. Nifedipine induced a concentration-dependent [0.01-1 μmol/L] increase in [Ca2+]iand NO formation in cultured porcine aortic endothelial cells, and moreover a dose- dependent NO formation in native endothelial cells from intact porcine coronary arteries, which was higher than in cultured cells. This effect was inhibited by N-nitro-L-arginine, a spe cific NO synthase inhibitor. Bay K 8644 caused a [Ca2+]iincrease and NO release in cul tured cells, too, although to a lesser extent. Nifedipine-induced and Bay K 8644-induced [Ca2+]irise could be blocked by removal of extracellular calcium, indicating that a calcium influx may be involved.

Conclusions: The calcium antagonist nifedipine as well as the calcium agonist Bay K 8644 cause an increase of [Ca2+]iand NO in porcine endothelium. Therefore, these effects seem to be related to the dihydropyridines as a substance class, which may explain the endothe lial component in dihydropyridine-induced vasorelaxation.
State-of-the-Art Review : Elevated Tissue Factor Levels in Leukemic Cell Homogenate
Authors: Nakasaki Takahiro , Wada Hideo , Watanabe Rika , Mori Yositaka , Gabazza Esteban C. , Kageyama Shinichi , Nishikawa Masakatu , Shiku Hiroshi
Published: November 2007

Tissue factor (TF) antigen and activity were mea sured in leukemic cell homogenates. In leukemic cell homog enate, especially that of acute promyelocytic leuekmia (APL), both TF antigen and activity were significantly higher than these levels in the mononuclear cells obtained from healthy volunteers. Both TF antigen and activity were significantly higher in myelocytic leukemia than in lymphocytic leukemia cells. In leukemic cell homogenates, there was a close corre lation between TF antigen and TF activity. The TF activity/TF antigen ratio was significantly higher in myelocytic leukemia than in lymphocytic leukemia cells. As the TF activity was not increased in lymphocytic leukemia cell homogenates to which were added phospholipids, the decrease in TF activity in lym phocytic leukemia might not be due to phospholipid in the leukemic cell membrane. Values for TF activity, TF antigen, and the TF activity/TF antigen ratio in leukemic cell homog enate from patients with disseminated intravascular coagulation (DIC) were significantly higher than those in patients without DIC. Therefore, the measurement of TF antigen and activity in leukemic cells could be useful for the prediction of DIC.
State-of-the-Art Review : Coagulation Tests and Anti-Phospholipid Antibodies in Patients Positive for Lupus Anticoagulant
Authors: Sakakura Miho , Wada Hideo , Watanabe Rika , Mamamuro Miho , Okugawa Yoshinaga , Nakasaki Takahiro , Nakase Tutomu , Wakita Yoshihiro , Minamikawa Kouzou , Mori Yositaka , Nshikawa Masakatsu , Shiku Hiroshi
Published: November 2007

We examined activated partial thromboplastin time, kaolin clotting time, mixing with normal plasma in kaolin clotting time, dilute Russell's viper venom time, dilute Rus sell's viper venom time at high lipid concentrations, anti phospholipid antibodies, and anti-cardiolipin-β2-glycoprotein I complex antibody in 135 patients with prolongation of acti vated partial thromboplastin time and diagnosed 86 patients positive for lupus anticoagulant. The sensitivity of activated partial thromboplastin time and dilute Russell's viper venom time/dilute Russell's viper venom time-high lipid concentra tions ratio for lupus anticoagulant were markedly high, but the specificity of activated partial thromboplastin time for lupus anticoagulant was not markedly high. The specificity, but not the sensitivity, of kaolin clotting time-mixing with normal plasma in kaolin clotting time was markedly high. In summary, dilute Russell's viper venom time to dilute Russell's viper venom time-high lipid concentrations ratio gave high sensitiv ity as well as specificity, being the only assay to confirm this. Of the patients positive for lupus anticoagulant, 25% were posi tive for anti-phospholipid antibodies and 17% were positive for anti-cardiolipin-β2-glycoprotein I complex antibody. Of the lu pus anticoagulant-positive patients with thrombosis, 45% were positive for anti-phospholipid antibodies, 35% were positive for anti-cardiolipin-β2-glycoprotein I complex antibody, 60% were positive for both anti-phospholipid antibodies and anti cardiolipin-β2-glycoprotein I complex antibody, and only 17% were negative for anti-phospholipid antibodies and anti cardiolipin-β2-glycoprotein I complex antibody. These find ings suggest that lupus anticoagulant can be diagnosed by di lute Russell's viper venom time/dilute Russell's viper venom time-high lipid concentrations ratio, and that thrombosis in lupus anticoagulant-positive may be predictable from both anti-phospholipid antibodies and anti-cardiolipin-β2- glycoprotein I complex antibody. Plasma tissue type plasmin ogen activator level in lupus anticoagulant patients was signifi cantly increased, and plasma tissue type plasminogen activator and fibrin-D-dimer levels in lupus anticoagulant-positive pa tients with thrombosis were significantly higher than in those without thrombosis, suggesting that the diagnosis of thrombo sis by hemostatic markers might be important in lupus antico agulant.
State-of-the-Art Review : Congenital and Acquired Thrombotic Risk Factors in Women Using Oral Contraceptives: Clinical Aspects
Authors: Mira Yolanda , Aznar Justo , Estellés Amparo , Vayá Amparo , Villa Piedad , Ferrando Fernando
Published: November 2007

We describe the thrombophilic and clinical char acteristics of a group of patients who suffered venous throm bosis (VT) ( n = 36) and ischemic stroke ( n = 8) while taking oral contraceptives (OC). Our purpose is to ascertain whether there are differences between users of second and third gen eration progestogen and to investigate the influence of concur rent congenital and acquired risk factors (other than OC) on the onset of the thrombosis. The group of patients included 36 women with VT and eight with ischemic stroke. The patients' recognized predisposing factors were recorded. We also con sidered age, length of time on OC, types of OC, rethrombosis, family history of VT, and the presence of thrombophilic genetic defects. In the group of patients with VT, 54% were treated with second generation OC ( n = 23), and 30% ( n = 11) were treated with third generation OC. We found no significant sta tistical differences with respect to age and length of time on OC between the two types of OC. The prevalence of genetic defects in these patients—factor V (FV) Leiden, prothrombin G20210A mutation and protein S deficiency—was 19% ( n = 7), 17% ( n = 6), and 8% ( n = 3) respectively. We observed the shortest time lapse between initiating OC and the first thrombotic event in carriers of FV Leiden and in patients with combined defects, but the differences were not significant. In patients with ischemic stroke, 50% were treated with second generation OC and 50% were treated with third generation OC. Prothrombin G20210A mutation was detected in two patients. In both patients,the stroke occurred earlier than in the rest of the patients, but these differences were not statistically significant. With respect to preventing thrombotic events in these patients, our data suggest that OC therapy should be avoided in patients with a previous history of thrombosis and in patients with an evident thrombotic tendency in the family. In patients in whom the family history of thrombosis is not very evident, it would be recommended to screen for FV Leiden, prothrombin G20210A mutation, and protein S, and to rule out OC if the patient does in fact have one of these risk factors. Moreover, if a patient develops a thrombotic complication while taking OC, an evalu ation to search for a thrombophilic defect is warranted, and at the same time, alternative methods of contraception should be considered.
Decreased Protein C Activation Is Associated With Abnormal Collagen Turnover in the Intraalveolar Space of Patients With Interstitial Lung Disease
Authors: Yasui Hiroki , Gabazza Esteban C. , Taguchi Osamu , Risteli Juha , Risteli Leila , Wada Hiroshi , Yuda Hisamichi , Kobayashi Tetsu , Kobayashi Hiroyasu , Suzuki Koji , Adachi Yukihiko
Published: November 2007

Activation of the coagulation system in the alveo lar space plays an important role in the pathogenesis of inter stitial lung disease (ILD) and pulmonary fibrosis. The protein C (PC) pathway is the main modulator of coagulation activation. This study evaluated whether dysfunction of the PC pathway is associated with increased collagen synthesis in the intraalveolar space of patients with ILD. This study comprised 22 patients with ILD; of these, five had idiopathic pulmonary fibrosis (IPF), nine had sarcoidosis-associated ILD, and eight had col lagen vascular disease-associated ILD (CVD-ILD). Thrombin— antithrombin complex (TAT) was measured as a marker of coagulation activation. As markers of the PC pathway activity, the concentration of activated PC-PC inhibitor (APC-PCI) complex and the APC-PCI/PC ratio were measured and, as a marker of collagen synthesis, the concentration of aminotermi nal propeptide of type III procollagen (PIIINP) was measured in bronchoalveolar lavage fluid (BALF) of ILD patients. TAT was significantly increased in BALF from ILD patients as com pared to control subjects. The concentrations of PIIINP were significantly elevated in patients with ILD as compared to healthy subjects. In contrast, the concentration of APC-PCI and the values of APC-PCI/PC ratio were significantly de creased in BALF from patients with ILD. BALF concentration of PIIINP was significantly and inversely correlated with the concentration of APC-PCI and with the APC-PCI/PC ratio. These findings suggest that dysfunction of the protein C path way may have important physiopathologic implications in the development of pulmonary fibrosis in ILD.
Plasma Tissue Factor Pathway Inhibitor Levels as a Marker for Postoperative Bleeding After Enoxaparin Use in Deep Vein Thrombosis Prophylaxis in Orthopedics and General Surgery
Authors: Hakki Sam I. , Fareed Jawed , Hoppensteadt Debra A. , Abdullah Hani , Camblin John , Nasseri Andrew F. , Hamadeh Ossama , Wright Terry
Published: November 2007

Low-molecular-weight heparins (LMWH) are widely used as antithrombotic prophylactic pharmaceutical agents in orthopedic and general surgery. Their antithrombotic characteristics are expressed by plasma mediators such as anti- Xa, anti-IIa, and increased release of tissue factor pathway inhibitor (TFPI) from vascular endothelium. The purpose of this clinical research is to study the relation between plasma levels of these mediators and postoperative bleeding.

Forty-one consecutive patients undergoing hip or knee ar throplasty (n = 36) and colectomy (n = 5) received the stan dard enoxaparin (a LMWH) dose preoperatively (general sur gery) or immediately postoperatively (orthopedic surgery). Ma jor bleeding was defined as a postoperative drop of ≥ 5 g/dL) of hemoglobin. The authors observed that there was a linear relationship between an increase in free/total TFPI ratio levels and postoperative bleeding. When that ratio increased by >60%, the hemoglobin dropped to >5 g/dL (n = 17).

This relationship between free/total TFPI ratio increase and postoperative bleeding was statistically significant ( P < 0.001). Those who did not bleed (hemoglobin drop was less than 5 g/dL) (n = 24) had a ratio increase (if any) of less than 50%. However, the authors did not observe any statistical relation ship between anti-Xa, anti-IIa, or prothrombin time and post operative bleeding in patients receiving LMWH for deep vein thrombosis prophylaxis in orthopedic and general surgery pa tients. The authors recommend a pre- and postoperative ratio level measurement whenever major bleeding is anticipated, as adjustments of LMWH dose or frequency might be necessary.
Platelets Expressing P-Selectin and Platelet-Derived Microparticles in Stored Platelet Concentrates Bind to PSGL-1 on Filtrated Leukocytes
Authors: Nomura Shosaku , Okamae Fumiko , Abe Misao , Hosokawa Mika , Yamaoka Manabu , Ohtani Tetsuji , Onishi Shuji , Matsuzaki Tatsunori , Teraoka Atsuko , Ishida Tomoko , Fukuhara Shirou
Published: November 2007

The levels of interleukin-6 and platelet-derived microparticles (PMPs) were measured in the blood of 137 pa tients with side effects from platelet concentrate (PC) transfu sion with leukocyte removal filtration, P-selectin-expressing platelet and PMPs in stored PC before and after the filtration, and filtered leukocytes positive for P-selectin glycoprotein li gand-1. The side effects, which were observed in 203 transfu sions for 84 patients with hematologic disease and 53 patients with nonhematologic disease with no significant difference be tween the two groups, included urticaria (75.9%), erythema (18.7%), and fever (17.2%), but no anaphylactic reactions. The levels of interleukin-6 and PMP correlated in both groups, and were significantly higher in the hematologic disease group than in the nonhematologic disease group. The level of PMP, but not interleukin-6, was significantly higher for patients testing posi tive for allergic reaction than for those testing negative. In the stored PC prior to filtration, the level of interleukin-6 was normal. The level of P-selectin-expressing platelets and PMPs was elevated before filtration, but was significantly lower after filtration. Taken together, the results suggest that PMP is in volved in the generation of transfusion reactions, and indicate that both platelets and PMP displaying P-selectin bind to P- selectin glycoprotein ligand-1 of leukocytes retained by the leukocyte filter.
Plasma and Platelet von Willebrand Factor Abnormalities in Patients With Uremia: Lack of Correlation With Uremic Bleeding
Authors: Casonato A. , Pontara E. , Vertolli U.P. , Steffan A. , Durante C. , De Marco L. , Sartorello F. , Girolami A.
Published: November 2007

Chronic renal failure often is associated with abnormal bleeding that may represent an important complication of this disorder. The hemorrhagic tendency currently is attributed to altered primary hemostasis, mainly platelet dysfunction. However, von Willebrand factor (vWF) also seems to be involved, even though the nature of its abnormalities is still controversial. To gain insight into the role of vWF in determining uremic bleeding, we studied II patients with stable, chronic renal failure. We found a significant increase in plasma factor VIII (FVIII), vWF:antigen (Ag), and vWF:ristocetin cofactor (Rco) levels, associated with a mean decrease in platelet vWF:Ag. Plasma vWF multimer pattern was characterized by increased representation of all oligomers in all patients, but five patients also showed a slight decrease in large vWF multimers. In addition, platelet vWF multimer pattern displayed a decrease in all components, especially those with high molecular weight. Despite normal bleeding time, collagen-induced platelet aggregation was defective in almost all patients, whereas vWF collagen binding capacity was normal. The levels of glycocalicin, the circulating fragment of glycoprotein Ib-IX, the major platelet vWF receptor, were also normal. In six patients who also were studied after initiation of dialysis, coliagen-induced platelet aggregation was impaired further. Moreover, plasma vWF, and especially FVIII levels, were increased additionally, in association with a normalized platelet vWF content and an improved vWF multimer pattern. The results suggest that vWF abnormalities are present in uremia. Moreover, thrombopathy caused by impaired collagen-induced platelet aggregation is constantly present and apparently not improved by dialytic treatment.
Prevention of Venous Thromboembolism: Recommendations Based on the International Consensus and the American College of Chest Physicians Sixth Consensus Conference on Antithrombotic Therapy
Authors: Haas Sylvia
Published: November 2007

The primary purpose of a Consensus Conference is to provide informed guidance on treatment decisions, assisting clinicians to make the optimal therapeutic choice for the patient, and providing protection against unjustified malpractice actions. The First American College of Chest Physicians (ACCP) Consensus Conference took place in 1985 and, using a systematic approach, provided recommendations for antithrombotic therapy based on published studies, and graded those recommendations on the level of clinical evidence. The European Consensus Conference was convened in 1991 to build on this process. During this period, the main developments included the introduction and widespread use of new thromboprophylactic agents such as low-molecular-weight heparins; and improved risk assessment, including an awareness that outpatients and general medical patients may also be at risk. Subsequently, the recommendations have been carefully reviewed and updated by experts who represent the extensive range of opinions in the field. The latest International Consensus Statement was published in 1997, and the most recent ACCP Consensus in 2001 and they provide extensive practice guidelines in the management of venous thromboembolism.
Plasma Markers of Endothelial Dysfunction in Chronic Obstructive Pulmonary Disease
Authors: Cella Giuseppe , Sbarai Alessandra , Mazzaro Gabriella , Vanzo Barbara , Romano Silvia , Hoppensteadt Debra , Fareed Jawed
Published: November 2007

We studied some endothelial cell activity plasma markers, nitric oxide (NO), thrombomodulin (TM), selectins (sP-, sE-,sL-selectin:platelet-P, endothelium-E, leukocyte-L), and tissue factor pathway inhibitor (TFPI) in 14 patients with chronic obstructive pulmonary disease (COPD), matched with 20 normal controls, to evaluate their endothelial cell dysfunction. Both NO (patients: 23.42 ± 1.67 μg/mL; controls: 40.0 ± 3.38 μg/mL) and TM levels (patients: 5.46 ± 1.32 ng/mL; controls : 12.9 ± 0.51 ng/mL) were significantly decreased in COPD (p < 0.001). sP-selectin levels (patients: 79.42 ± 18.20 ng/mL, controls: 37.5 ± 2.84 mg/mL) were significantly higher (p < 0.02), whereas sL-selectin levels (patients: 584.9 ± 78.98 ng/mL, controls: 1054.02 ± 61.28 ng/mL) were significantly decreased in patients with COPD (p < 0.001). In contrast, no differences were seen in sE-selectin. Patients with COPD showed a significantly higher (p < 0.001) TFPI antigen plasma level (mean 112.28 ± 6.45 ng/mL; controls 77.68 ± 0.28 ng/mL) than controls. Our data support the concept of some form of endothelial cell dysfunction, and coagulation abnormalities are present in patients with COPD. However, because the endothelium seems to produce a defense mechanism, the potential usefulness of an antithrombotic therapy in these patients needs further investigation.
Platelet Functions in Patients With Protein-Energy Malnutrition
Authors: Üner Abdurrahman , Çalişkan Ümran , Öner Ahmet Faik , Koç Hasan , Kasap Ali Fazli
Published: November 2007

Protein-energy malnutrition (PEM) has been known to cause several organ damages or dysfunctions. In this study, using optic method, platelet aggregation (PA) analyses were performed in patients with PEM. Adenosine diphosphate (ADP)- and collagen-induced PA were significantly decreased in the patients with PEM. The low values reached normal when the patients caught up the optimal growing curve for their age. PA with ristocetin and epinephrine were not significantly altered in the patients. Conversely, mean platelet count was increased at the beginning compared to those of after therapy and to the control. These results indicate that some platelet functions (ADP- and collagen-induced platelet aggregations). as well as other body functions, have been decreased in PEM.
Use of a Low-Molecular-Weight Heparinoid (Danaparoid Sodium) for Continuous Renal Replacement Therapy in Intensive Care Patients
Authors: Lindhoff-Last Edelgard , Betz Christoph , Bauersachs Rupen
Published: November 2007

The purpose of this study was to evaluate the efficacy and safety of danaparoid in the treatment of critically ill patients with acute renal failure and suspected heparin-induced thrombocytopenia (HIT) needing renal replacement therapy (RRT). We conducted a retrospective analysis of 13 consecutive intensive care patients with acute renal failure and suspected HIT who were treated with danaparoid for at least 3 days during RRT. In eight patients, continuous venovenous hemofiltration was performed. The mean infusion rate of danaparoid was 140 ± 86 U/hour. Filter exchange was necessary every 37.5 hours. In five patients, continuous venovenous hemodialysis was used. A bolus injection of 750 U danaparoid was followed by a mean infusion rate of 138 ± 122 U/hour. Filters were exchanged every 24 hours. In 7 of 13 patients, even a low mean infusion rate of 88 ± 35 U/hour was efficient. Mean anti-Xa (aXa) levels were approximately 0.4 ± 0.2 aXa U/mL. Persistent thrombocytopenia despite discontinuation of heparin treatment was observed in 9 of 13 patients, owing to disseminated intravascular coagulation (DIC). HIT was confirmed by an increase in platelet count and positive heparin-induced antibodies in 2 of 13 patients. No thromboembolic complications occurred, but major bleeding was observed in 6 of 13 patients, which could be explained by consumption of coagulation factors and platelets due to DIC in 5 of 6 patients. Nine of 13 patients died of multiorgan failure or sepsis, or both. In none of these patients was the fatal outcome related to danaparoid treatment. In critically ill patients with renal impairment and suspected HIT, a bralus injection of 750 U danaparoid followed by a mean infusion rate of 50 to 150 U/hour appears to be a safe and efficient treatment option when alternative anticoagutation is necessary.
Hemophilia A, von Willebrand Disease, and Atherosclerosis of Abdominal Aorta and Leg Arteries: Factor VIII and von Willebrand Factor Defects Appear to Protect Abdominal Aorta and Leg Arteries From Atherosclerosis
Authors: Bilora F. , Boccioletti V. , Zanon E. , Petrobelli F. , Girolami A.
Published: November 2007

We hypothesized that patients with hemophilia or von Willebrand disease might be protected from atherosclerosis because of their coagulation defect. We studied 40 subjects affected by these two coagulation diseases using echocolor Doppler of the abdominal aorta and leg arteries, and compared the results with those obtained in 40 control patients who were homogenous with study patients in terms of sex, age, and risk factors for atherosclerosis. The probands presented a lower number of plaques than the 40 control subjects in the aorta and in the leg arteries. The most serious hemophilic patients had fewer plaques than controls or than patients with mild hemophilia. Both hemophilia and von Willebrand disease seem to protect against atherosclerosis.
Fatal Pulmonary Arterial Thrombosis Associated With Chlorine Gas Poisoning
Authors: Suzuki Shunji , Sakamoto Susumu , Maniwa Kohji , Saitoh Atsushi , Hirayama Yasutaka , Kobayashi Hiroko , Matsuo Takefumi
Published: November 2007

We present a patient with accidental chlorine gas poisoning who died from pulmonary thrombosis due to a marked increase in hemostatic factors such as von Willebrand factor after recovering from the acute poisoning.
A Sensitive DRVVT Reagent System for the Detection of Lupus Anticoagulants
Authors: Joyner Kelly A. , Ortel Thomas L.
Published: November 2007

Lupus anticoagulants are antibodies that inter fere with the phospholipid-dependent steps in in vitro blood clotting. The dilute viper venom (DVV)test is a phospholipid-limiting assay in which a plasma sample is preactivated with the venom from the pit viper Vipera russelli, which contains specific activators for factors X and V. A diluted sample of purified phospholipid and cal cium ions is added, and the clotting time is determined. If the DVVtest is prolonged, a DVVconfirm is then per formed. An excess of phospholipid is added to the test mixture of patient plasma and DVVtest sample. In most patients with lupus anticoagulants (LACs), addition of excess phospholipid will (partially) correct the prolonged DVVtest. We investigated a new formulation of the DV Vtest and DVV confirm that consisted of a more purified phospholipid reagent system. Twenty-six normal donors had negative results in both assays. A group of 42 patients were compared using the old and new formulations of the DVVtest and DVVconfirm. Thirty-six patients had agree ment of results between the old and new formulations. Of the six remaining samples, five that had been negative with the old formulation were positive with the new for mulation. Of these five, three of three had a positive an ticardiolipin antibody by enzyme-linked immunosorbent assay. The last patient was positive with the old formu lation and negative with the new, but this patient had a negative anticardiolipin antibody. Therefore, these re sults suggest that the new formulation of the DVVtest and DVV confirm is more sensitive to the presence of LACs.