bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of the Electrophysiologic Actions of E-4031 and Dofetilide by Hyperkalemia and Acidosis in Rabbit Ventricular Myocytes
Authors: West Paul D. , Martin Donald K. , Bursill Jane A. , Wyse Kenneth R. , Campbell Terence J.
Published: November 2007

Background: E-4031 and dofetilide are new class III antiarrhythmic agents that inhibit the rapid component of the delayed rectifier potassium channel (IKr); however, the effectiveness of many antiarrhythmic drugs in ischemic conditions is uncertain.

Methods and Results: We modeled two components of ischemia, hyperkalemia (9.6 mM) and acidosis (pH 6.8), in voltage-clamped single rabbit ventricular myocytes to help deter mine the effect of ischemia on the action of these two drugs. In physiologic solution both E- 4031 and dofetilide blocked IKr and significantly reduced total outward current. In hyper kalemic solution, both E-4031 and dofetilide showed significantly reduced blockade of IKr, while in acidotic solution dofetilide showed significantly reduced blockade of IKr and E-4031 showed a trend to reduced blockade. Neither drug significantly reduced total outward current in hyperkalemic or acidotic solutions.

Conclusions: In these conditions, E-4031 and dofetilide demonstrate reduced blockade of I Kr, resulting in loss of class III effect. Furthermore, the complete loss of blocking effect on total outward current during simulated ischemia suggests increases of other repolarizing cur rents also contribute to loss of class III effect.
Atorvastatin, a New HMG-CoA Reductase Inhibitor, Does Not Affect Glucocorticoid Hormones in Patients with Hypercholesterolemia
Authors: Isaacsohn Jonathan L. , Bakker-Arkema Rebecca G. , Fayyad Rana , Whitcomb Randall , Black Donald M.
Published: November 2007

Background: Atorvastatin calcium (Lipitor) is a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. The present study was conducted to examine the effect of pronounced cholesterol lowering on adrenal function in patients with severe hypercholes terolemia.

Methods and Results: Adrenal function was examined under basal conditions and following adrenal corticotropin hormone stimulation in 40 patients (36 with heterogeneous familial and 4 with polygenic hypercholesterolemia). The study was part of a larger study comparing the efficacy and safety of atorvastatin, colestipol, atorvastatin + colestipol, and simvastatin + colestipol treatment over a 1-year period. Maximum doses of all agents were studied: 80 mg atorvastatin once daily, 40 mg simvastatin once daily, and 20 g/day colestipol. At the end of the 1-year treatment period, reductions in low-density lipoprotein cholesterol were 57%, 54%, and 49% for the atorvastatin, colestipol + atorvastatin, and colestipol + simvastatin groups, respectively. No clinically significant changes in basal serum cortisol levels were seen in any treatment group during the 1-year treatment period. Mean serum cortisol concen trations and area under the curve for cortisol concentration versus time data following adrenal corticotropin hormone stimulation were not clinically different during treatment compared with values obtained at baseline for any of the treatment groups.

Conclusions: Treatment with maximum doses of atorvastatin for 1-year did not have any adverse effects on adrenal function under basal conditions or during maximum stimulation. Similarly, colestipol therapy alone and in combination with either atorvastatin or simvastatin did not appear to affect adrenal function.
Frequency-dependent Cardiac Electrophysiologic Effects of Tedisamil: Comparison With Quinidine and Sotalol
Authors: Németh Miklós , Varró András , Virág László , Hála Ottó , Thormählen Dirk , Gyula Papp Julius
Published: November 2007

Background: Tedisamil is a potent bradycardic/antiischemic drug known to lengthen car diac repolarization by blocking various potassium channels. Recent in vivo experiments revealed that it is an antiarrhythmic agent. It was therefore of interest to compare the cellu lar electrophysiologic effects of tedisamil with those of quinidine and sotalol in isolated car diac preparations.

Methods and Results: The conventional microelectrode technique was applied in isolated dog cardiac Purkinje and ventricular muscle fibers and in rabbit left atrial muscle. Tedisamil (1 μM) and sotalol (30 μM) lengthened, while quinidine (10 μM) shortened action potential duration in dog Purkinje fibers. The phase 1 repolarization was delayed by tedisamil and quinidine and not changed by sotalol. In dog ventricular muscle and in rabbit atrial muscle, all three drugs studied lengthened repolarization. In dog Purkinje fiber, tedisamil and sotalol lengthened action potential duration more at slow than at high stimulation frequency (reverse use-dependence). In dog ventricular muscle fibers, the effect of the drugs was not clearly fre quency dependent. In rabbit atrial muscle fibers, the quinidine-evoked repolariration length ening was most pronounced at intermediate cycle lengths (500-1000 ms). Tedisamil and quinidine but not sotalol depressed the maximal rate of depolarization (Vmax), which depended on the stimulation frequency (use-dependence). The nature of the use-dependent Vmax block differed between quinidine and tedisamil. Quinidine decreased Vmax at a relatively wide range of stimulation frequencies while tedisamil decreased Vmax largely at high rate of stimulation. Tedisamil and quinidine prevented or decreased the pinacidil-evoked action potential shortening in dog ventricular muscle, suggesting block of the ATP-dependent potas sium channels (IKATP), while with sotalol such effect was not observed.

Conclusions: Although tedisamil, quinidine. and sotalol are known to lengthen the QT inter val, their cellular electrophysiologic effects substantially differ. Tedisamil lengthens repolar ization and prevents pinacidil-evoked action potential duration shortening, suggesting IK(ATP) blockade. Its effect on the Vmax is limited mostly to fast heart rate. These electrophysiologic effects of tedisamil resemble those of chronic amiodarone treatment.
Review : Recent Advances in the Prevention of Coronary Artery Disease: Focus on Primary Prevention
Authors: Sudhir Krishnankutty
Published: November 2007

Background: Several new strategies for prevention of coronary artery disease have emerged. This review examines the various approaches to primary prevention, and some aspects of secondary prevention.

Methods and Results : The role of aspirin, beta-blockers, exercise, diets, fish intake, vitamin E, and folic acid are discussed. The potential role of chlamydia in atherosclerosis, the pro tective effect of alcohol consumption, and the benefits of female sex hormones are also examined. An update on lipid-lowering therapy, and a summary of the recent major clinical trials establishing the use of 3-hydroxy-3-methylgluataryl-coenzyme A reductase inhibitors in primary and secondary prevention of coronary artery disease, are provided.

Conclusions: An aggressive approach to medical management of coronary artery disease a substantial reduction in risk.
Mechanisms of Impaired Endothelial Function Associated with Insulin Resistance
Authors: Miller Allison Winecoff , Hoenig Margarethe E. , Ujhelyi Michael R.
Published: November 2007

Background: The insulin-resistant (IR) syndrome is causally related to hypertension and cardiovascular events; however, the underlying mechanism remains elusive. The current study was designed to determine (1) whether the IR syndrome causes vascular dysfunction and (2) whether insulin resistance alters the activity of the individual endothelium-derived relaxing factors.

Methods and Results: Insulin resistance was induced in Sprague-Dawley rats by a 4-week fructose-rich diet. Subsequently, mesenteric arteries (~250 μM) were removed from control and 1R rats, and intraluminal diameter was used to assess vascular response to pharmaco logical probes. Studies with sodium nitroprusside showed that vascular relaxation did not differ between IR and control groups. In contrast, maximal vascular relaxation to acetylcho line (10 -9 to 10-4 mol/L) in phenylephrinc preconstricted arteries was decreased in the IR group (44 ± 4%) versus control (89 ± 5%) ( P < .01). N-nitro-L-arginine (LNNA) pretreat ment further impaired acetylcholine-induced maximal relaxation in the IR group from 44 ± 4% to 12 ± 3%; P < .01. In control rats, maximal relaxation was only slightly impaired by the addition of LNNA (89 ± 5% to 68 ± 6%; P <.05). The addition of indomethacin to ace tylcholine did not affect maximal relaxation in either group. When potassium chloride (KCl) was used for preconstriction, relaxation to acetylcholine in the IR group was similar to that found with phenylephrine preconstriction (41 ± 4% v 44 ± 4%, respectively); how ever, KCl preconstriction significantly decreased acetylcholine-induced relaxation in con trol rats (89 ± 5% to 43 ± 5%; P > .01).

Conclusion: Insulin resistance impairs endothelium-dependent relaxation in small mesen teric arteries. It appears that insulin resistance transforms the primary relaxant factor from endothelial-derived hyperpolarizing factor to nitric oxide. These findings suggest that hyper tension and atherosclerosis associated with the IR syndrome are caused, at least in part, by endothelial dysfunction.
Significance of Supraventricular Tachyarrhythmias After Coronary Artery Bypass Graft Surgery and Their Prevention by Low-Dose Sotalol: A Prospective Double-Blind Randomized Placebo-Controlled Study
Authors: Klöter Weber Uta , Osswald Stefan , Buser Peter , Huber Maurus , Skarvan Karl , Stulz Peter , Pfisterer Matthias
Published: November 2007

Background: The single most frequent complication after coronary artery bypass graft surgery is the occurrence of supraventricular tachyarrhythmias leading to a prolonged hospital stay. Although several drugs have been used to treat these arrhythmias, effective prevention was only possible with beta-blocking drugs in selected patients. It was, therefore, the aim of the present study to evaluate the significance of supraventricular tachyarrhythmias in presence of today's cardioprotective management in a broad spectrum of patients and to assess the possible preventive effect and safety of low-dose sotalol after coronary artery bypass graft surgery. Methods and Results: In a prospective randomized double-blind placebo-controlled trial, 220 consecutive patients referred for elective coronary artery bypass graft surgery were random ized to 80 mg sotalol twice daily (n = 110) or matching placebo (n = 110) for 3 months with the first dose given 2 hours before surgery. There were no significant differences in baseline charac teristics between the two groups. Low-dose sotalol reduced the rate of supraventricular arrhythmias from 43% (placebo) to 25% (sotalol, P <.01), which was atrial fibrillation in 83%, flutter in 7%, and other supraventricular arrhythmias in 10%. Only 7% of all arrhythmias were observed after day 9. Hospital stay was I 1 ± 4 days in patients with supraventricular arrhyth mias versus 9 ± 2 days ( P < .001) in patients without. On the fourth postoperative day, heart rate was lower in the sotalol group (75 ± 12 versus 86 ± 14 beats per min; P < .0001), but QTc was not significantly prolonged (sotalol, 0.44 ± 0.03; placebo 0.43 ± 0.03; P. ns). Study medica tion had to be discontinued due to side effects in 6.4% of sotalol and 3.6% of placebo patients (P. ns), but relevant side effects occurred only in two sotalol patients late after surgery. Conclusions: These data show that without antiarrhythmic therapy the incidence of supraventricular arrhythmias after coronary artery bypass graft surgery is high (43%) and that supraventricular arrhythmias were associated with a prolonged hospital stay (+2 days). Prophylactic treatment with low-dose sotalol reduced the incidence of supraventricular arrhythmias significantly (by 40%), thereby reducing overall hospital stay in treated patients. Because more than 90% of all supraventricular arrhythmic episodes occurred within 10 days after surgery and considering the small proarrhythmic effect of sotalol late after surgery, prophylactic treatment with sotalol may be recommended for the first 10 postoperative days to safely reduce supraventricular tachyarrhythmias.
Risk Factors for Tachycardia Events Caused by Antiarrhythmic Drugs: Experience From the ESVEM Trial
Authors: Sharma Param P. , Ott Peter , Hartz Vernon , Mason Jay W. , Marcus Frank I.
Published: November 2007

Background: In the Electrophysiology Study versus Electrocardiographic Monitoring (ESVEM) trial, up to seven antiarrhythmic drugs were randomly assigned to 486 patients with a history of sustained ventricular arrhythmia. At baseline, all the patients had inducible sustained ventricular tachycardia (VT) and had ≥10 premature ventricular beats (PVBs) per hour on 48-hour Holter monitoring. A total of 1,229 drug trials were performed. Antiar rhythmic drugs were discontinued during hospitalization because of ventricular tachy arrhythmias thought to be a proarrhythmic effect of the antiarrhythmic drugs in 96 of 479 patients (20%) who received drugs. Proarrhythmic effects were defined as sustained VT, ventricular fibrillation or arrhythmic death, torsade de pointes, or distinct intolerable wors ening of the baseline arrhythmia after at least three doses of the drug.

Methods and Results: Eighteen baseline characteristics were analyzed for factors that would predict a higher incidence of proarrhythmia. These included type of heart disease, previous myocardial infarction, symptom activity scale, gender, type of arrhythmia, VT/ ventricular fibrillation, age, left ventricular ejection fraction (LVEF), PVB frequency, heart rate, QRS duration, and QT interval. Multiple logistic regression analysis identified increased mean PVB frequency ( P = .003) and increased heart rate ( P = .026) as significant predic tors of proarrhythmia. Decreased LVEF (<25%) exhibited only a trend toward significance ( P = .073). When proarrhythmia was redefined as sustained VT, cardiac arrest or arrhyth mic death, or torsade de pointes (n = 59), PVB frequency ( P = .003) and heart rate ( P = .034) were still the only significant baseline predictors.

Conclusion: In the ESVEM study, higher PVB frequency and higher heart rate were signif icant predictors of drug-induced proarrhythmia.
State-of-the-Art-Review : The Leiden Mutation of Coagulation Factor V in Hungarian SLE Patients
Authors: Regéczy Nóra , Lakos Gabriella , Balogh István , Ajzner Eva , Kiss Emese , Szegedi Gyula
Published: November 2007

We studied the prevalence and the effect of coagu lation factor V Leiden mutation on the occurrence of throm botic episodes in 120 Hungarian patients having systemic lupus erythematosus (SLE) with or without antiphospholipid anti body.

The frequency of the factor V Leiden mutation in Hungarian SLE patients was 13%, which is comparable with those found previously in a healthy Caucasian population. The incidence of venous thrombosis among factor V Leiden carriers has been found to be higher (odds ratio [OR] 1.7) than it is in patients without Leiden mutation (38% vs 29%). In addition, the fre quency of venous thrombosis in the heterozygous SLE patients (OR 8.4 [confidence interval (CI) 0.8-83.9] P=0.06) is depen dent on the coexistence of other risk factors, such as antiphos pholipid antibody. Moreover, among heterozygous factor V SLE patients, the Leiden mutation could explain the tendency to have significantly higher prevalence of fetal losses (OR 3.9 [CI 1.2-12.0] P = 0.02) and higher prevalence of cerebrovascu lar lesions, cardiac valvular abnormalities, and Raynaud's syn drome than that found in individuals without factor V Leiden mutation or those having antiphospholipid antibody.

Systemic lupus erythematosus patients with combined de fects suffer more severely from thrombosis than those with a single risk factor do, suggesting that thrombophilia is a multi- factorial disorder in SLE, also. Although, the factor V Leiden mutation does not seem to be a significant risk factor for ve nous thrombosis in SLE, these data demonstrate that Leiden mutation can be regarded as an additive thrombogenic factor providing higher predisposition to several vasoocclusive disor ders in SLE.
Platelet Prothrombinase Activity, a Final Pathway Platelet Procoagulant Activity, Is Overexpressed in Type 1 Diabetes: No Relationship With Mean Platelet Volume or Background Retinopathy
Authors: van der Planken Marc G. , Vertessen Francine J. , Vertommen Jan , Engelen Wendy , Berneman Zwi N. , De Leeuw Ivo
Published: November 2007

There is overwhelming evidence that platelets from diabetic individuals are hyperreactive, not only when mi crovascular complications are apparent, but already at an early stage of the disease. There is still controversy about the ques tion of whether primary hyperreactive platelets may contribute to the origin or progression of microangiopathy or whether diabetic platelet hyperfunctionality is just a logical conse quence of a continuous low-grade activation of platelets by contact with a diseased microvascular wall. As a consequence of platelet activation, the outer layer of its phospholipid mem brane is more procoagulant than in the quiescent state, stimu lating thrombin formation in plasma. This platelet function is called platelet procoagulant activity. We studied platelet pro thrombinase activity (PPA), a final pathway platelet procoagu lant activity of type 1 diabetic platelets, and looked for an eventual correlation with microvascular disease (background retinopathy) and mean platelet volume (MPV). Stypven clot ting times (SCTs), reflecting PPA expression, and MPV of citrated platelet-rich plasma (PRP), were measured in 21 pa tients with type 1 diabetes—10 with and 11 without back ground retinopathy—under clinically acceptable metabolic control and compared them to 20 disease-free voluntary con trols. We also compared PPA expression and MPV in diabetic individuals with and without retinopathy. With the SCT, a se lective test adapted for studying PPA in PRP, we found hyper expression of PPA in all diabetic patients. We found no differ ence in MPV between diabetic and control PRP. Comparing patients with and without background retinopathy we found no significant difference in PPA expression. From these results, we suggest that the phospholipid surface of diabetic platelets, more than the surface of normal control platelets, stimulate the expression of PPA. This diabetic platelet coagulant anomaly was not related to an increased platelet mass (higher MPV) nor to the presence of microangiopathy. We conclude that PPA hyperexpression is associated with patients with type 1 diabe tes, already occurring in an early stage of the disease, and not necessarily a consequence of early-stage microvascular disease, because the anomaly is also demonstrable, in the same degree, in patients with diabetes without microangiopathy.
Singlet Oxygen Inhibits Agonist-Induced P-Selectin Expression and Formation of Platelet Aggregates
Authors: Stief T.W. , Jeske W.P. , Walenga J. , Schultz C. , Kretschmer V. , Fareed J.
Published: November 2007

Major mediators of activated polymorphonuclear leukocytes (PMN) are the oxidants HOCl and chloramine, which are a source for the nonradical photon-emitting oxidant singlet oxygen (1O2). We were interested in a possible platelet-modulating activity of 1O2, As a stable 1O2 source we chose the mild oxidant chloramine T® (CT), which mimics the natural chloramine N-chloro-taurine. Freshly drawn native whole blood from donors (n = 5) was incubated at 0 to 3 mM CT for I minute at 37°C. Then saline, 10 μM adenosine diphosphate (ADP), 5 μg/mL collagen, or 6.25 μM thrombin receptor activator peptide (TRAP) were added and the mixtures were allowed to incubate for 3 minutes at 37°C. Aliquots of activated blood were fixed in 1% para-formaldehyde. After removal of the fixative, platelets were labeled with anti-CD61-FITC and anti-CD62P-PE antibodies and analyzed by flow cytometry. An oxidant concentration-dependent decrease in the expression of -selectin appeared (at 3 mM CT to 39, 23, and 20% of the 100% saline control level for ADP, collagen, and TRAP, respectively). There was also an oxidant concentration-dependent decrease in the formation of platelet aggregates (at 3 mM CT to 8, 12, and 13% of the 100% saline control level for ADP, collagen, and TRAP, respectively; the 50% effective dose was 1.0 to 1.5 mM chloramine). In ADP- and TRAP-stimulated platelets, an oxidant-mediated increase in platelet fragments appeared (at 3 mM CT: three- to fourfold of the initial value). The addition to the blood of 30 mM of the oxy-radical scavenger mannitol in contrast to excess methionine did not antagonize these oxidative modulations of platelet activation. The results were confirmed using equimolar concentrations of NaOCl and N-chloro-taurine. This study shows that 1O2 inhibits platelets, decreasing the expression of CD62P and the formation of platelet aggregates. Activated PMN might modulate hemostasis, shifting it into an antithrombotic state. The physiologic signal action and the direct anticoagulant action of 1O2 (released by chloramines such as vancomycin) might be a new principle for pharmacologic intervention in atherothrombosis.
Molecular Markers of Hemostatic Activation: Applications in the Diagnosis of Thrombosis and Vascular and Thrombotic Disorders
Authors: Fareed Jawed , Bick Rodger L. , Hoppensteadt Debra A. , Bermes Edward W.
Published: November 2007

The recognition of molecular marker events leading to hemostatic and thrombotic disorders and technologic advances in molecular biology and immunology has added a new dimension in the diagnosis of bleeding and thrombotic disorders. Pathophysiologic activation of coagulation, fibrinolysis, kallikrein-kinin system, vascu— lar stress, and intercellular interactions result in the generation of cell/process specific markers of a pathophysiologic event. It has been two decades since the concept of molecular markers was first introduced in the diagnosis of hemostatic and thrombotic disorders. However, due to cost/technologic limitations and lack of understanding of this field at various levels its usage in clinical laboratory diagnosis was rather limited. With the advent of such analytical techniques such as enzyme-linked immunosorbent assays (ELISA) a disease specific molecular profiling can be readily accomplished. Subclinical activation of platelets, endothelial distress, and aberrations of the protease network can be readily diagnosed by utilizing specific assays. The concept of hypercoagulable state is now validated utilizing such markers of hemostatic activation such as platelet factor 4, thromboxane B2, fibrinopeptide A and plasminogen activator inhibitor. Cardiovascular disease risk and blood vascular disorders can be diagnosed utilizing these markers. The monitoring of antithrombotic drugs that do not produce any anticoagulant effects on blood can also be readily accomplished by using some of these lanalytes. Using specific monoclonal antibodies, various diagnostic profiles for such disorders as thrombotic stroke, disseminated intravascular coagulation, primary fibrinolysis, hemodynamic disorders, and diseases of vascular origin can be investigated. Since the introduction of this concept some 50 additional markers have been introduced. The recognition of tissue factor pathway inhibitor (TFPI) has introduced a new concept in the understanding of the plasmatic and vascular interactions. Tissue factor and its inhibitor can now be measured at fmol amounts in plasma and body fluids. Specific antibodies to these markers can also be utilized in immunocytometric and flow cytometric analysis and will provide valuable diagnostic information. High through-put instruments and cost/technologies compliance methodologies are available to provide affordable laboratory approaches in the new era of cost constraint diagnostic medicine. However, a major deficit in the educational programs still exists and warrants the development of these programs in medical and allied health curriculums. Key Words: Molecular markers—Hypercoagulable state—Enzyme-linked immunosorbent assay—Tissue factor pathway inhibitor— Tissue factor.
Assessment of Relative Contributions of Fibrinolysis and Fibrinogenolysis to the Abnormalities of Plasma Fibrinogen/Fibrin-Retated D and E Antigens and Their Ratio in Liver Cirrhosis
Authors: Soon Song Kyung , Lee Anna , Kwon Oh Hun
Published: November 2007

Many pathogenic mechanisms play a part in hemorrhage in chronic liver disease. This study was done to characterize the alterations of fibrinogen components and dysfibrinogenemia in patients with liver cirrhosis. Plasma from 31 patients with liver cirrhosis was analyzed to determine the fibrinogen/fibrin-related D and E antigens by latex photometric immunoassay; fibrinogen by the Clauss method; fibrinogen degradation product (FgDP), protein C antigen, and tissue plasminogen activator (tPA) by enzyme immunoassay; and antithrombin III by the colorimetric method, respectively. Reptilase, time and fibrin monomer (FM) tests were also done. Fibrinogen/fibrin-related D and E antigens were higher and their ratio (D/E) was lower in liver cirrhosis compared with normal subjects. Fibrinogen levels were inversely correlated with D (p = 0.0001) and E (p = 0.0001) antigenic levels in plasma. FgDP levels were not significantly correlated with D and E levels. However, semiquantitative D-dimer levels had significant association with D and E levels. Reptilase time was abnormally prolonged in all patients with high D and E levels, and FM tests were also positive in most patients with increased levels of D and E. Protein C antigen levels were inversely correlated with D (p = 0.0110) and E (p = 0.0112) concentrations but were well correlated with clottable fibrinogen concentrations (p = 0.0058). Hypercoagulability followed by pathologic activation of fibrinolysis, rather than synthesis of abnormal fibrinogen molecules, may contribute to hemorrhage. Not only true hypofibrinogenemia due to the decreased synthesis of intact fibrinogen but also elevated levels of these antigens may be clinically significant in the treatment of cirrhotic patients at risk of bleeding. Protein C may play an important regulatory role in fibrinolysis.
Coagulation and Fibrinolysis During the First Year of Immunosuppressive Treatment in Renal Transplantation: Correspondence Between Hypercoagulable State and Steroid Therapy
Authors: Patrassi Giovanni Maurizio , Sartori Maria Teresa , Rigotti Paolo , Di Landro Domenico , Perin Antonella , Theodoridis Panagiotis , Saggiorato Graziella , Casonato Alessandra , Girolami Antonio
Published: November 2007

An increased incidence of thromboembolic complications has been reported after kidney transplantation, and hypercoagulability has been associated with immunosuppressive treatment, specifically with Cyclosporin A. Hypercorticism due to prolonged steroid therapy or to Cushing's disease has been associated with a similar hypercoagulable state and thrombotic risk. The aims of this study were first to evaluate coagulation and fibrinolytic behavior in 27 patients at different times during the first year after renal transplantation and then to compare the same patients' coagulation and fibrinolytic findings 1 month after transplantation with those of a normal control group and a group of Cushing's patients. Compared with normal controls, renal transplant patients and Cushing's patients showed a similar hypercoagulable and hypofibrinolytic state, with a significant shortening in activated partial thromboplastin time and increase in factor VIII-von Willebrand factor complex, tissue plasminogen activator concentration, and plasminogen activator inhibitor activity and concentration. Other test results in the two groups showed no differences. The same abnormalities were present in the renal transplant group for the entire period of study. Our results suggest that a hypercoagulable and hypofibrinolytic state persists almost 1 year after renal transplantation and that these abnormalities are very similar to those present in Cushing's disease. Steroid treatment seems to play a key role in determining thromboembolic risk after renal transplantation. Key Words: Renal transplantation-Hypercoagulable state—von Willebrand factor-Hypofibrinolysis-Plasminogen activator inhibitor-Steroid therapy-Cyclosporin A.
Relevance of Inherited Risk Factors in Young Patients with Deep-Vein Thrombosis
Authors: Cogo Alberto , Lensing Anthonie W. A. , Prandoni Paolo , Simioni Paolo , Bernardi Enrico , Girolami Bruno , Piccioli Andrea , Villalta Sabina , Wouter ten Cate Jan , Girolami Antonio
Published: November 2007

The relevance of congenital thrombophilia in the pathogenesis of venous thromboembolism in young patients is still debated. In a case-control study, plasma antigen and activity of antithrombin, protein C, and plas minogen, as well as total and free protein S were mea sured in a series of 166 consecutive outpatients aged less than 50 years, who underwent contrast venography be cause of clinically suspected deep-vein thrombosis (DVT). The presence of major acquired risk factors for venous thrombosis was also recorded. The association between DVT and inherited thrombophilia or acquired risk factors was initially described using crude odds ratios (OR). Subsequently, a logistic regression model was used to test their independence. Of the 166 patients included, venography showed an acute DVT in 73 (cases), whereas it was normal in the remaining 93 (controls). Major ac quired risk factors were identified in 51 cases and in 20 controls (crude OR: 8.5; 95% CI: 4.1-17.1). Inherited thrombophilia was detected in seven cases and in one control (crude OR: 9.8; 95% CI: 1.2-81.2). Inherited thrombophilia was equally distributed between patients with secondary and idiopathic DVT and was proved to be independent from acquired risk factors in the regression model. Inherited thrombophilia is an independent risk factor for DVT in young patients. However, its preva lence in unselected cases with the first episode of DVT is low.
Prevalence of Antiphospholipid Antibodies and Lupus Anticoagulant in Juvenile Patients with Objectively Documented Deep-vein Thrombosis
Authors: Zanon E. , Saracino M.A. , Simioni Paolo , Cogo Alberto , Fadin M.A. , Gavasso S. , Girolami Antonio
Published: November 2007

The prevalence of lupus anticoagulant (LA) and antiphospholipid antibodies (APA) in young patients (<45 years) with deep-vein thrombosis (DVT) is not clearly defined yet. We studied 93 consecutive patients (36 males, 57 females; aged 15 to 45) with objectively documented DVT. A control group consisting of 100 nor mal, sex- and age-matched individuals was also investi gated. In all subjects, we evaluated prothrombin time (PT), partial thromboplastin time (PTT), AT III antigen and activity, protein C antigen and activity, free and total protein S antigen and protein S activity, fibrinogen, plas minogen, heparin cofactor II, plasminogen activator in hibitor (PAI), lupus anticoagulant (LA), and APA. For the assessment of LA, we used the PTT-LA kit (Boeh ringer Mannheim, Milan, Italy) as a screening test, with mixing studies with the Staclot-PNP kit and the Staclot- LA kit (Boehringer Mannheim, Milan, Italy) as confirma tory procedures. For the detection of APA, we used a commercially available enzyme-linked immunoassay (ELISA) (Asserachrom APA, Boehringer Mannheim, Mi lan, Italy). History was elicited in all patients to deter mine if the thrombotic episode was idiopathic or the re sult of a well-identified risk factor. LA was found in 11 (11.8%) patients. APA were positive in 13 (14%) and bor derline in 19 (20.4%) patients. In the control group, no patients were positive for LA or APA, but five exhibited borderline APA levels. LA was significantly more fre quent (p = 0.05) in patients with idiopathic DVT than in patients with secondary DVT; no difference was found for APA (p > 0.5). An inherited coagulation defect was found in seven (7.5%) patients. Our data suggest that the presence of LA or APA is associated with an increased incidence of thrombotic manifestation in young patients. Moreover LA is more frequent in patients with idiopathic DVT. Because the incidence of recurrent thrombotic manifestations in patients with LA or APA is estimated to be ∼50% within 2 years from the first thrombotic episode, the tests should be performed in all patients with juvenile thrombosis.
Effect of Low-Molecular-Weight Heparin (Tinzaparin) and Unfractionated Heparin on Platelet Aggregation
Authors: Ravn Hanne B. , Bregengaard Claus , Vissinger Henrik , Østergaard Per , Holst Jan , Nielsen Hans K. , Kristensen Steen D. , Husted Steen E.
Published: November 2007

A low-molecular-weight heparin (LMWH), when anti-IIa activity was compared. In the ex vivo part Tinzaparin, was compared with unfractionated heparin of the study, a significant enhancement of ADP-induced (UFH) for their effects on platelet aggregation in vitro and platelet aggregation was observed after i.v. administra ex vivo. Both heparins showed a dose-dependent proag- tion of both Tinzaparin and UFH with no difference in gregatory effect on ADP- and collagen-induced platelet potency. Subcutaneous administration of Tinzaparin in aggregation in vitro, but LMWH was less potent. The two different doses did not have any effect on platelet differences in potency between Tinzaparin and UFH de- activity. In conclusion, Tinzaparin appears, like other pended on how the compounds were compared. The most LMWHs, to have less proaggregatory effect on platelets pronounced difference was found when molar concentra- than UFH both in vitro and ex vivo.
A Case of Acquired Idiopathic Hemophilia Successfully Treated with Immunosuppressive Drugs and Factor VIII Concentrates
Authors: Bucalossi Alessandro , Marotta Giuseppe , De Regis Franco , Galieni Piero , Dispensa Egidio
Published: November 2007

The appearance of circulating factor VIII:C (FVIII:C) inhibitors in nonhemophilic patients represents a rare condition characterized by spontaneous and often life-threatening bleeding. We describe a patient with ac quired idiopathic hemophilia in whom immunosuppres sive therapy associated with human FVIII infusion deter mined a prompt and complete disappearance of the inhib itor. Given the very low number of patients with acquired hemophilia and the lack of prospective randomized clin ical trials published, we hope to contribute to a better definition of the therapeutic strategy in these patients.
New Method for Quantifying Lupus Anticoagulant
Authors: Speck Roy
Published: November 2007

A method is presented using a new reagent containing propylgallate for the quantitative determina tion of lupus anticoagulant. The amount of an optimized phospholipid standard required by the clotting reaction was found to be 32-50 μg/ml at a 95% confidence level, with a mean of 41 μg/ml. This method eliminates the ef fect of heparin therapy, coumadin therapy, factor-VIII inhibitor, factor-IX inhibitor, and single-factor deficien cies that afflict presently used lupus anticoagulant screen ing and confirmatory procedures. Using this method, it should be possible to detect lupus anticoagulant in pa tients at a much lower level and follow the effect of ther apy on lupus anticoagulant.
Citric Acid Enhances the Antithrombotic Effect of Aspirin in Many Aspirin-Resistant Subjects
Authors: Kaplan Svetlana , Kaplan Alexander , Marcoe Karen F. , Hammond William P. , Fisher Lloyd D. , Sauvage Lester R.
Published: November 2007

This study had three objectives: (1) to determine the frequency of high platelet aggregators in a consecutive series of 268 apparently healthy volunteers who presented to our Center; (2) to assess the inhibitory effect of aspirin (ASA) on these high aggregators; (3) to determine, in a double-blind trial, whether or not the addition of citric acid (CTA) to ASA would increase its inhibitory effect in subjects who had a suboptimal response to aspirin alone. A platelet aggregation-scoring methodology developed for turbidimetric platelet aggregometry was used to quantify baseline aggregation and medicinal effects. We define a high aggregator as one whose unmedicated PA score is ≥30. We define the response of a high aggregator to ASA as poor if the medicated PA score stays at ≥30. We found that 58 of 268 apparently healthy unmedicated volunteers (22%) had PA scores ≥30. and that 27 of these (47%) had a poor response to 325 mg ASA, with an average drop in their PA scores from 49.5 ± 13.1 to 41.1 ± 8.6 (16%). Twenty-five of these 27 people were enrolled in the double-Mind study comparing the effect of ASA and ASA + CTA on platelet aggregability. Of these high aggregators who had a poor response to ASA, 12 of 25 (50%) had a good response to 162.5 mg of ASA plus 162.5 mg of CTA, with an average drop of their PA scores from 46.7 ± 13.2 to 22.0 ± 5.2 (53%). CTA alone had no effect on the PA score, which was similar to the control placebo. Our data suggest that a 1:1 combination of ASA and CTA may offer significantly greater protection agairtst arterial thrombotic events than ASA alone in subjects who respond poorly to ASA. Key Words: Platelet aggregation—Antithrombotic medication—Thrombosis.
Some Hemostatic Changes During the Course of Hemodialysis in Patients with Erythropoietin Treatment
Authors: Staško Ján , Funiak Stanislav , Funiaková Sona , Peterková Mária , Ivanková Jela , Makovický Pavol , Kubisz Peter
Published: November 2007

The recombinant human erythropoietin (rHuEPO), an effective agent in the treatment of renal anemia, can predispose chronic uremic patients to thrombotic events with regular hemodialysis (HD). It has been proposed that increased release of tissue plasminogen activator (t-PA) from endothelial cells, together with consumption of plasminogen activator inhibitor-1 (PAI- 1), is likely to be a leading cause of enhanced fibrinolytic activity (FA) during HD. In our study, rHuEPO-treated patients manifested PAI-1 Ag (antigen) plasma levels that were significantly augmented after HD, suggesting FA inhibition during the HD session. The elevated predialysis beta-thromboglobulin (BTG) and platelet factor-4 (PF-4) plasma levels were increased in rHuEPO-treated patients during HD; the platelet protein levels were simultaneously decreased in the control group. Both findings reflect decreased FA and greater activity of platelets in the course of HD with administration of rHuEPO and a possible correlation of these mechanisms with the questioned prothrombotic performance of rHuEPO. Key Words: Erythropoietin—Hentodiatysts—Fibrinotytic activity—Platelet proteins.
Modified Technique for Measuring Platelet Aggregation
Authors: Kaplan Alexander , Kaplan Svetlana , Marcoe Karen F. , Sauvage Lester R. , Hammond William P.
Published: November 2007

The turbidimetric method of Bom is the current approach for assessing the aggregation behavior of platelets. It has been of modest practical value, due to difficulty in standardizing laboratory techniques for plasma preparation and inadequate quantification of the aggregation process. We report a new technique of sedimented platelet rich plasma (SPRP) preparation that reduces the irregularities caused by factors associated with procuring and preparing blood samples and permits a more flexible protocol for laboratory practice. We quantified results with a platelet aggregation score, which is calculated by multiplying the ratio of the height of the initial wave of aggregation to the maximum height of the aggregation pattern by the total area under the aggregation curve and by the ratio of the whole blood platelet count and the number of platelets in the sample. Comparative analysis of platelet aggregation scores (n = 95) obtained with both plasma preparation techniques using a paired t test demonstrated no statistical differences ( t = 1.368, p = 0.174). To demonstrate the application of this modified method to evaluation of antiplatelet agents, the effects of aspirin and aspirin combined with citric acid on platelet aggregation were studied in vitro. The antiaggregatory effect of aspirin combined with citric acid was dependent on the pH and on their molar ratio, and was greater than the effect of aspirin alone. The SPRP protocol with platelet aggregation scoring methodology could be a valid alternative for measurement of the platelets' propensity to aggregate and the effect of antithrombotic treatments. Key Words: Platelet aggregation— Aspirin—Citric acid.
Antiplatelet Effects of the Addition of Acetylsalicylic Acid 40 Mg Daily to Ticlopidine in Human Healthy Volunteers
Authors: Lecompte Thomas P. , Lecrubier Chantal , Bouloux Cyril , Horellou Marie-Hélène , Galleyrand Jacques , Maffrand Jean-Pierre , Samama Meyer M.
Published: November 2007

Clinical studies have shown that acetylsalicylic acid (ASA) or ticlopidine (T) bring a partial clinical benefit in a subset of patients threatened by thrombosis on atherosclerotic plaques. Acetylsalicylic acid and T have different impacts on platelet function and the combination of the drugs seems logical to achieve a greater antiplatelet effect. Healthy volunteers were randomly allocated to any of the three treatment groups: T 250-placebo; T 250-T 250; placebo-placebo (treatment was administered in a double blind manner). Acetylsalicylic acid 40 mg was openly administered once a day to the subjects of the three groups after the first week of treatment. Simplate I bleeding time and platelet aggregation testing were performed before treatment and at the end of the two treatment periods. We confirmed that T alone prolongs bleeding time and impairs, in a dose-dependent manner, ADP-induced aggregation; platelet responses that depend on released ADP were also affected. Inhibition of thromboxane-dependent aggregation, associated with a doubling of the bleeding time, was observed after one week of low-dose ASA inhibition of thromboxane synthesis. An additive effect of ASA 40 mg to T 250 mg on the bleeding time was evidenced. There was also a wider alteration of platelet aggregation, with a trend towards an inhibition of the response to a high concentration of collagen as compared to ASA or T used alone. Such a powerful, logical drug combination is in good agreement with preliminary encouraging results obtained after coronary stent implantation and deserves further studies in patients at high risk for arterial thrombosis to define its benefit-risk profile. Key Words: Aspirin—Ticlopidine— Drug combination—Bleeding time—Platelet aggregation.
Thrombosis and Hemostasis in Cardiology: Review of Pathophysiology and Clinical Practice (Part II)
Authors: Baker William F.
Published: November 2007

The adverse consequences of thrombosis are per haps nowhere more evident than in clinical cardiology. Throm bosis and hemostasis are primary issues in the management of patients with atrial fibrillation, prosthetic heart valves, severe left ventricular dysfunction, and coronary artery disease. Clini cal trials have defined a crucial role for anticoagulation with warfarin in patients with atrial fibrillation to reduce the inci dence of stroke. Anticoagulation with warfarin and aspirin in combination offers significant protection from systemic emboli in patients with mechanical prosthetic valves, without a sub stantial increased risk of hemorrhage. The risk of systemic emboli may also be reduced by anticoagulation in patients with severe left ventricular dysfunction. Disturbance of the normal balance of hemostasis is a major factor in the pathophysiology of coronary artery disease. Antiplatelet therapy, antithrombin agents, anticoagulants, and fibrinolytic agents have been used to prevent and treat acute coronary thrombosis and to prevent reocclusion following thrombolysis and interventional therapy. Guidelines are presented for antithrombotic therapy in the prac tice of clinical cardiology. Key Words: Thrombosis— Cardiology—Coronary artery disease—Atrial fibrillation— Valvular heart disease.
Antithrombin Agents as Anticoagulants and Antithrombotics: Implications in Drug Development
Authors: Fareed Jawed
Published: November 2007

Antithrombin agents of recombinant and synthetic origin are now validated in experimental models as useful an ticoagulant and antithrombic drugs. Several clinical trials in cluding surgical anticoagulation, management of coronary syn dromes, adjunct to thrombolytic agents and treatment of throm boembolism have also shown the comparative efficacy of these agents in reference to heparin. Argatroban and hirudin are now available for specific clinical indications such as thrombotic and ischemic stroke and alternate anticoagulants for heparin- induced thrombocytopenia (HIT) patients in Japan and Euro pean countries, respectively. While these agents produce strong anticoagulant effects, their mechanism of action is distinct from that of heparins, thus these agents should be used carefully using specific guidelines provided for each product. Thrombin inhibitors are effective anticoagulants however, their therapeu tic index is narrower than heparin and as such their nonopti mized use is potentially associated with hemorrhagic compli cations.
Asymptomatic Homozygous nt 20210 G to A Prothrombin Polymorphism in Two Blood Donors Belonging to Two Different Kindreds
Authors: Girolami Antonio , Simioni Paolo , Manfrin Davide , Tormene Daniela , Luni Sonia
Published: November 2007

The nucleotide (nt) 20210 G to A prothrombin polymorphism has been associated with an increased incidence of thrombosis, particularly venous thrombosis. The increased incidence of thrombosis resulted from an increase in prothrom bin levels. Two homozygous patients with this abnormality were found to be completely asymptomatic. In one of the two cases there was no thrombosis even after the additional risk factor of oral contraceptive therapy for several months. Pro thrombin activity and antigen as assayed by several methods were at the upper limits of normalcy in one case and slightly elevated in the other. The two cases described in this article do not rule out the possibility that this prothrombin abnormality be associated, given special acquired circumstances, with throm bosis. However, they indicate that extreme caution is needed to avoid an inaccurate conclusion. The fact that homozygous pa tients may remain asymptomatic indicates that the prothrom botic defect is very mild, if any. Key Words: Prothrombin— 20210 G to A abnormality—Thrombosis—Polymorphism.
Thrombotic Risk of Muscular Dystrophy: Protein C Deficiency, Factor V Leiden, and Myotonic Dystrophy
Authors: Cobos Everardo , Phy Michael , Yi Kong Keung
Published: November 2007

While patients with hereditary muscular disorder are more sedentary and believed to be at risk of thrombosis, there is little literature on thrombosis associated with hereditary muscular disorder. We report a rare case of double heterozy gous type I protein C deficiency and factor V Leiden in a patient with classic myotonic dystrophy.
Significant hypersensitivity with paclitaxel managed by a 50 hour infusion
Authors: Nakashima Lynne , Keller Oliver , Speck Shelley , Swenerton Kenneth
Published: November 2007

Paclitaxel is a new antineoplastic agent isolated from the bark of the Western Yew tree. It can be associated with hypersensitivity reactions. Usually these reactions are prevented through the use of a premedication regimen including dexamethasone, diphenhydramine, and cimetidine. Some patients, however, have difficulty tolerating the paclitaxel despite premedication. We report the case of a patient who developed a hypersensitivity reaction to paclitaxel. We were able to administer the paclitaxel by extending the infusion time to ap proximately 50 hours. This strategy could poten tially be used for patients whose hypersensitivity reaction appears rate related.