bluuebunny/crossref_metadata_2025 huggingface dataset:
Pinacidil's Effects on Defibrillation Outcomes: Role of Increased Potassium Conductance Via the KATP Channel
Authors: Winecoff Allison P. , Sims J. Jason , Markel Michael L. , Ujhelyi Michael R.
Published: November 2007

Background: It has been shown that the inhibition of potassium ion conductance decreases defibrillation threshold. We postulated that if potassium conductance is a primary mechanism affecting defibrillation threshold values, then increasing potassium ion conductance will increase defibrillation values. The primary objective of this study was to determine if the ATP-dependent potassium (KATP) channel opener pinacidil would increase defibrillation threshold values. The second objective was to prove that the observed changes were due to potassium conductance by using the KATP inhibitor, glyburide, to reverse the electrophysio logic actions of pinacidil. The third objective was to determine if the electrophysiology actions of pinacidil correlate with changes in defibrillation threshold value.

Methods and Results: Domestic farm swine (n = 14) were anesthetized and intubated. Subsequently, they were instrumented with monophasic action potential catheters and epi cardial defibrillation patches. Defibrillation threshold values, action potential duration, effective refractory period, and ventricular fibrillation cycle length were determined at base line and during treatment phase 1 and treatment phase 2. Pigs were randomized into 2 groups: group 1 (n = 6) received D5W in treatment phase one followed by D5W in treatment phase 2 and group 2 (n = 8) received pinacidil in treatment phase one followed by the addi tion of glyburide in treatment phase two. DFTED50 did not change at baseline, treatment phase one or treatment phase two for group 1 (10.5 ± 2, 11.1 ± 1.7, 10.5 ± 1.0 J) or for group 2 (10.1 ± 2.2, 11.4 ± 4.2, 11.4 ± 3.0 J). Electrophysiologic parameters (QRS, effec tive refractory period, action potential duration 90, and ventricular fibrillation cycle length) were not significantly changed from baseline in group 1. In contrast, effective refractory period, action potential duration90, and ventricular fibrillation cycle length significantly decreased at all recorded sites after the administration of pinacidil in group 2 (range of 7-13%, 6-9%, and 12-17%, respectively). However, pinacidil did not change the basal level of dispersion in effective refractory period, action potential duration, and ventricular fibrillation cycle length during paced rhythm or ventricular fibrillation. Glyburide reversed pinacidil's electrophysiologic actions.

Conclusions: Pinacidil does not alter defibrillation threshold, but it reduces effective refractory period, action potential duration, and ventricular fibrillation cycle length and does not increase electrical heterogeneity. Therefore, changes in potassium channel conductance as well as short ening repolarization are unlikely primary mechanisms for elevating defibrillation threshold.
Electrophysiologic Effects of the New Class III Antiarrhythmic Drug Dofetilide in an Experimental Canine Model of Pacing-induced Atrial Fibrillation
Authors: Feld Gregory K. , Yongmei Cha
Published: November 2007

Background: Dofetilide is a new class III antiarrhythmic drug currently under investigation for the treatment of supraventricular arrhythmias in humans. Dofetilide have been previously shown to be highly effective in terminating and suppressing reentrant atrial flutter in the experimental canine crush-injury model, in which its antiarrhythmic efficacy was correlated with prolongation of wavelength and reduction in dispersion of refractoriness, effects not produced by the class IA antiarrhythmic drug quinidine. The purpose of this study was to evaluate the antiarrhythmic efficacy and mechanisms of action of dofetilide in an experimen tal model of atrial fibrillation.

Methods and Results: Dofetilide was administered intravenously to seven open-chest dogs with acute sustained atrial fibrillation induced by rapid atrial pacing for up to 4 hours. Mean atrial effective refractory period (ERP), dispersion of ERP, conduction velocity and wave length were determined by multipoint right atrial programmed stimulation and activation mapping using a 56-electrode mapping plaque on the right atrial free wall. Dofetilide pro longed average ERP by 22% from 104 ± 13 to 127 ± 15 ms ( P < .001), prolonged maximum ERP by 11% from 129 ± 7 to 143 ± 10 ( P < .003), had no effect on conduction velocity at 200 ms pacing cycle length, slowed conduction velocity by 16% from 0.89 ± 12 to 0.75 ± .17 ms at 150 ms pacing cycle length ( P < .001), increased wavelength by 20% from 93 ± 7 to 112 ± 9 mm ( P < .01), reduced dispersion of ERP by 24% from 11.4 ± 2.9 to 8.7 ± 2.3 ( P = .016), and reduced the number of adjacent electrodes with ERP difference ≥20 ms by 67% from 18.4 ± 7.1 to 6.1 ± 4.2 ( P < .001). Dofetilide reduced the number of excitation wavelets (total over three beats) entering the region of the mapping plaque by 38% from 5.0 ± .8 to 3.1 ± .4 ( P < .002). Dofetilide terminated atrial fibrillation in all seven dogs at a mean of 3.4 ± 2.2 minutes into the loading infusion and prevented reinduction of atrial fibrillation in all seven dogs after completion of the loading infusion, while on maintenance infusion. Time to termination of atrial fibrillation correlated closely with change in ERP ( r = 0.78, P = .036). Conclusions: Dofetilide was highly effective in terminating and suppressing sustained pac ing induced atrial fibrillation in this canine model. Time to termination of atrial fibrillation correlated with the degree of change in ERP produced by dofetilide. The mechanism of ter mination of atrial fibrillation by dofetilide appeared to be a progressive reduction and even tual extinction of re-entrant wavelets. The predominant electrophysiologic effects of dofetilide were prolongation of ERP and wavelength and a reduction in dispersion of refrac toriness. Dofetilide had little effect on conduction velocity in this model, except at very short pacing cycle lengths.
Intravenous Propafenone for Conversion of Atrial Fibrillation or Flutter to Sinus Rhythm: A Randomized, Placebo-controlled, Crossover Study
Authors: Serdar Fak Ali , Tezcan Hakan , Caymaz Oguz , Tokay Sena , Oktay Şule , Oktay Ahmet
Published: November 2007

Background: Propafenone has been claimed to be effective in converting atrial fibrillation and flutter to sinus rhythm; however, controlled clinical trials have reported variable results, and data about the safety of propafenone in the setting of heart failure are lacking. The aim of the present study was to evaluate the efficacy and safety of intravenous propafenone in con verting atrial fibrillation and flutter to sinus rhythm.

Methods: Sixty patients with acute (< 72 h) or chronic atrial fibrillation or flutter were included in a randomized, placebo-controlled, conditional cross-over study. Twenty eight patients, of whom 12 were in New York Heart Association class III and IV, had heart failure. Patients received intravenous propafenone (2 mg/kg in 10 minutes) and placebo subsequently at 1 hour intervals if sinus rhythm was not achieved. The patients' rhythms were continuously monitored for 1 hour and a 12-lead electrocardiogram, a 1-minute continuous rhythm strip and vital signs were recorded at baseline and at 15, 30, 45, and 60 minutes after the adminis tration of each drug.

Results: Twenty of the 59 patients (34%) treated with propafenone converted to sinus rhythm, while only 4 of the 50 patients (8%) treated with placebo converted (P < .001). Propafenone was more effective in patients with acute (< 72 h) atrial fibrillation (64.5%). The conversion rate with propafenone was not significantly different from placebo in patients with atrial flutter and chronic atrial fibrillation (> 72 h). Propafenone significantly decreased ( P < .005 vs placebo) mean ventricular rate in nonresponders with a baseline heart rate of more than 100 beats/min. No clinically significant adverse effect occurred.

Conclusions: We conclude that intravenous propafenone treatment is effective for converting acute atrial fibrillation; however, it seems unlikely to be beneficial in atrial flutter and chronic atrial fiorillation. Propafenone decreases ventricular rate in nonresponders, and a single dose of propafenone is relatively safe even in moderate-to-severe heart failure.
Comparative Study of the Effects of Erythromycin and Roxithromycin on Action Potential Duration and Potassium Currents in Canine Purkinje Fibers and Rabbit Myocardium
Authors: West Paul D. , Martin Donald K. , Bursill Jane A. , Wyse Kenneth R. , Campbell Terence J.
Published: November 2007

Background: Erythromycin and roxithromycin are macrolide antibiotics in common clini cal use. Erythromycin occasionally produces life-threatening arrhythmias ( torsades de pointes) by blocking the outward potassium current responsible for repolarization of the cardiac action potential.

Methods and Results: We used standard cellular electrophysiological and whole-cell patch- clamping techniques to compare the relative efficacy of erythromycin and roxithromycin in prolonging cardiac action potential in canine Purkinje fibers and in blocking individual out ward potassium currents in isolated rabbit ventricular myocytes. We demonstrated signifi cant prolongation of action potential duration in canine Purkinje fibers by erythromycin but not roxithromycin at a concentration of 100 μM. The delayed rectifier, the outward potas sium current thought to be most sensitive to modulation by drugs, was significantly depressed by both agents at concentrations of ≥30 μM in isolated rabbit ventricular myo cytes. Both drugs had similar potencies (26% and 21 % reduction by 30 μM erythromycin and roxithromycin, respectively, and 50% and 36% reduction by 100 μM erythromycin and roxithromycin). Neither agent significantly blocked other potassium currents (including the transient outward current).

Conclusions: Taking into account normally observed peak blood concentrations of these agents in clinical use and the fact that roxithromycin is not normally administered intrave nously, we conclude that the risk of proarrhythmia during normal clinical use of oral roxithromycin is extremely remote.
Lysophosphatidylcholine and Cellular Potassium Loss in Isolated Rabbit Ventricle
Authors: Goldhaber Joshua I. , Deutsch Nicholas , Alexander Laura D. , Weiss James N.
Published: November 2007

Background: Lysophospholipids such as lysophosphatidylcholine (LPC) have many direct electrophysiological effects on cardiac muscle and have been implicated as a cause of lethal ventricular arrhythmias during acute myocardial ischemia. Because extracellular K + accu mulation is also a key arrhythmogenic factor during acute ischemia, we examined the effects of LPC on cellular K+ balance, including its interaction with adenosine triphosphate- sensitive K+ (KATP) channels.

Methods and Results : Isolated rabbit interventricular septa paced at 75 beats/min were loaded with 42K+ to measure unidirectional K+ efflux rate (in 42K- washout experiments) or tissue K + content (in 42K+ uptake experiments) and action potential duration (APD) during exposure to 20 μM LPC for 30 minutes. LPC caused tissue K+ content to decrease by 15 ± 2% (n = 4) at a steady rate over 30 minutes, associated with gradual APD shortening and a delayed increase in unidirectional K+ efflux rate. Pretreatment with 12 μM cromakalim to selectively activate KATP channels shortened APD by 44 ± 66% and had no effect on net tis sue K+ content during control aerobic perfusion. However, cromakalim increased net K+ loss during exposure to LPC to 22 ± 4%, a 47% increase.

Conclusions: LPC induced net K loss in heart, which was potentiated by the KATP channel agonist cromakalim. This ATP finding suggests that if LPC accumulates to similar levels during myocardial ischemia and hypoxia, it may be an important mechanism in net K+ loss.
A Multicenter, Placebo-Controlled, Dose-Ranging Study of Atorvastatin
Authors: Schrott Helmut , Fereshetian Anita Gmerek , Knopp Robert H. , Bays Harold , Jones Peter H. , Littlejohn Thomas W. , McLain Richard , Black Donald M.
Published: November 2007

Background: Coronary heart disease (CHD) is the number one cause of death in Western societies. Elevated levels of plasma low-density lipoprotein (LDL) cholesterol and triglycer ides (TG) increase the risk for CHD. 3-Hydroxy-3-methylglutaryl conenzyme A (HMG- CoA) reductase inhibitors effectively reduce plasma cholesterol levels in patients with hypercholesterolemia. This study assesses the safety and dose-related effects of atorvastatin calcium on lipoprotein fractions in patients with LDL cholesterol levels between 160 mg/dL (4.1 mM) and 250 mg/dL (6.5 mM) or less and TG levels of 400 mg/dL (4.5 mM) or less.

Methods and Results: Sixty-five patients were enrolled in a 6-week, randomized, placebo- controlled, parallel-group study. Patients received placebo or atorvastatin 10, 20, 40, 60, or 80 mg once daily. Adjusted mean decreases in LDL cholesterol for patients receiving ator vastatin 10, 20, 40, 60, and 80 mg were 37%, 42%, 50%, 52%, and 59%, respectively, com pared with a mean increase of 0.3% for patients receiving placebo; the differences between each of the atorvastatin dose groups and placebo were statistically significant ( P = .0001). Total cholesterol, triglycerides, and apolipoprotein B were significantly reduced in atorva statin groups ( P = .0001). Adverse events were similar in the placebo and atorvastatin treat ment groups. No patient had a serious adverse event or withdrew because of an adverse event during this study.

Conclusions: Atorvastatin effectively lowered plasma LDL cholesterol, triglycerides, and apoB levels in a dose-related manner. Atorvastatin was well tolerated in hyperlipidemic patients over a 6-week period.
Clinical Review : Update on Atrial Fibrillation: Restoration of Sinus Rhythm or Ventricular Rate Control?
Authors: Li Yi-Gang , Hohnloser Stefan H.
Published: November 2007

In patients with persistent atrial fibrillation, two therapeutic alternatives exist, namely res toration and maintenance of sinus rhythm versus ventricular rate control combined with anticoagulation. Currently, the selection of the best therapeutic strategy in an individual patient relies for the most part on clinical judgement and personal experience. At present, there are no prospective scientific data to support the superiority of one treatment over the other with respect to overall survival or quality of life. This review summarizes the present knowledge on this important clinical problem with particular emphasis on issues such as efficacy of antiarrhythmic drugs to prevent recurrent atrial fibrillation, proarrhythmic haz ards of these compounds, or efficacy and safety of anticoagulation in nonrheumatic atrial fibrillation. These data serve as the basis of ongoing clinical trials prospectively comparing the merits and demerits of the two therapeutic strategies in the most common arrhythmia encountered in clinical practice.
Initiating and Maintaining Patients on Warfarin Anticoagulation: The Importance of Monitoring
Authors: Ezekowitz Michael D. , James Kenneth E. , Radford Martha J. , Rickles Frederick R. , Redmond Nadia
Published: November 2007

Background: The VA Stroke Prevention in Nonrheumatic Atrial Fibrillation study was a prospective, randomized, double-blind study comparing low-dose warfarin with placebo in patients with nonrheumatic atrial fibrillation. The trial showed a 79% reduction in stroke rate in warfarin randomized patients without an increase in bleeding complications. We examined the need for frequent prothrombin time monitoring (international normalized ratios [INR] were not measured directly) in patients receiving warfarin.

Methods and Results: Patients were initiated on 4.0 mg/d warfarin with a goal of main taining the prothrombin time ratio (PTR) within the range of 1.2-1.5 (estimated INR: 1.4-2.8). PTR monitoring was performed weekly during a 12-week induction period and monthly thereafter for a total follow-up of 3 years. Two hundred sixty patients were ran domized to receive warfarin. During the induction period, the proportion of patients whose PTRs were in the desired range increased from 28% at 1 week postrandomization to 65% at 12 weeks postrandomization; the proportion of patients requiring a dose adjustment decreased from 52% to 16% during the same period. During the maintenance period, the mean proportion of patients whose PTRs were within 1.2-1.5 was 60.5% ± 6.2%.

Conclusions: Low-dose anticoagulation with warfarin in outpatients should be initiated at the anticipated maintenance dose. This approach reduces the chance of being out of range on the high side. Weekly INR estimation during this phase seems optimal. Considerable dose adjusting was required during the maintenance phase to keep patients within range; monthly INRs are required. Because of the need for dose adjustments, fixed-dose warfarin regimens are unlikely to keep patients in the desired narrow therapeutic range.
State-of-the-Art-Review : Statins Induce Hypothrombotic States?
Authors: Fenton John W. , Shen Garry X. , Minnear Fred L. , Brezniak Diane V. , Walenga Jeanine M. , Bognacki John J. , Ofosu Frederick A.
Published: November 2007

Statins inhibit 3-hydroxy-3-methyl-glutaryl coenzyme A (HMGCoA) reductase, which synthesizes mevalonic acid in the isoprenoid pathways. These pathways lead to squalene and subsequently to cholesterol and related products (e.g., steroids, vitamin D, bile salts, lipopro teins) and have major branches producing cell regulatory substances (e.g., farnesyl- and geranylgeranyl conjugated proteins) (1,2). Although cholesterol reduc tion in blood has been widely believed to be beneficial (e.g., less available for accumulation by foam cells in atherosclerotic plaques), the ability of cholesterol reduc tion to mitigate the incidence and severity of cardiovas cular diseases has recently been questioned. Like others (3-10), we (11) believe that statins and other substances, for example, plant isoprenoids in the diet (12), have ben eficial antithrombotic properties arising through the in hibition of an isoprenoid product other than cholesterol. However, unlike others, we also believe that this isopren oid product has cell regulatory functions upregulated by thrombin stimulation. Moreover, through such cellular pathways, thrombin should upregulate its own genera tion, and statins and dietary isoprenoids should induce hypothrombotic states by downregulating thrombin gen eration (Fig. 1).
State-of-the-Art-Review : The Antithrombotic Factor Singlet Oxygen/Light (1O2/hv)
Authors: Stief Thomas W. , Fareed Jawed
Published: November 2007

Activated phagocytes (especially polymorpho nuclear granulocytes (PMNs)) by respiratory oxidative/ photonic burst (activation of NADPH-oxidase and myeloper oxidase) generate large amounts of oxidants of the hypochlo rite-/chloramine-type, which are physiologic sources for singlet oxygen (1O2), a nonradical-excited (photon (hυ) emitting) oxy gen species [Weiss SJ, NEJM 1989;320:365-376]. In vitro ex periments show that 1O2 (1) inhibits coagulation by inactiva tion of thrombocytes, fibrinogen, factor V, factor VIII, and factor X and (2) activates fibrinolysis by inactivation of the main fibrinolysis inhibitors plasminogen activator inhibitor (PAI)-1 and alpha-2-antiplasmin, and by activation of single- chain urokinase by plasmin and oxidized fibrin. Additionally, this work suggests that 1O2/hυ acts antithrombotically, induc ing selective thrombolysis in vivo (i.e., thrombolysis induced by 0.1 to 0.5 mmol/l chloramine within 30 to 60 minutes with out changes of the plasmatic hemostasis system). 1O2 might activate flowing to (on the endothelium) rolling PMN, increas ing their chance to get in contact with fibrin/platelet aggregates deposited on the endothelial layer. Via 1O2 generation, the thrombus-activated phagocytes might call for (acute, physi ologic) inflammation/fibrinolysis amplification, resulting in the "moving front" of PMN, which infiltrates and destroys the thrombus. 1O2 seems to (partially) participate in the reactivity of nitric oxide, another prooxidative agent. The inhibition of physiologic amounts of 1O2 by blood cholesterol might be in volved in the pathogenesis of atherothrombosis. Consequently, it is suggested that activated PMNs modulate hemostasis, shift ing it into an antithrombotic state; this cellular part of fibrino lysis seems to be of greater physiologic importance than the plasmatic one. Impaired PMN function (e.g., as occurring in patients with antineutrophil cytoplasmic antibodies or under cytostatic treatments) often results in serious thrombotic com plications. Light is the only signal whose origin can be imme diately recognized by a fast moving cell in the (dark) blood stream. The cell signal action of 1O2/hυ (e.g., released by chlo ramines such as taurine-chloramine or vancomycin, by fiber- optic, by photodynamic therapy, or by so-called redox-cycling drugs such as quinones or tetracyclines) might be a new and physiologic principle for pharmacologic intervention in athero thrombosis.
Soluble P-Selectin in Human Plasma: Effect of Anticoagulant Matrix and its Levels in Patients With Cardiovascular Disorders
Authors: Amin Hesham M. , Ahmad Sarfraz , Walenga Jeanine M. , Hoppensteadt Debra A. , Leitz Helen , Fareed Jawed
Published: November 2007

P-Selectin represents a cell surface glycoprotein that is constitutively present in the Weibel-Palade bodies of endothelial cells and in the α-granules of platelets. In inflam mation and thrombogenic conditions, plasmatic P-selectin lev els are markedly elevated, indicating the leakage of this marker from these sites. In this study, a quantitative sandwich enzyme- linked immunosorbent assay (ELISA) utilizing a monoclonal soluble P-selectin (sP-selectin) antibody was employed to as sess this marker in blood samples collected in various antico agulants such as heparin, hirudin, sodium citrate (3.2% and 3.8%), and ethylenediaminetetraacetic acid (EDTA). The soluble P-selectin levels ranged from 26 ng/mL to 44 ng/mL. Sodium citrate (3.8%) was used to collect platelet-poor plasma (PPP) from patients with heparin-induced thrombocytopenia (HIT), coronary angioplasty (CA), or coronary atherectomy (CAT). In comparison with the control group (∼ 30 ng/mL), all of these patient groups showed a marked elevation of sP- selectin levels (HIT = 96 ng/mL [n = 18], CA = 46 ng/mL [n = 6] and CAT = 60 ng/mL [n = 10]). In platelet-rich plasma (PRP) preparations using various anticoagulants, the sP-selectin levels were markedly higher, ranging from 87 ng/ mL to 117 ng/mL (n = 10). In patients recruited into a clinical trial (the argatroban [ARG] 911 Study), in which argatroban was used as an alternate anticoagulant in patients with HIT, a 25% to 35% decrease in sP-selectin levels was observed after 72 hours of argatroban treatment. In addition, the relative ratio between levels in PRP and PPP in these patients differed, sug gesting that the anticoagulant matrix influences the sP-selectin levels. These data clearly suggest that the anticoagulant matrix and blood collection procedures may significantly influence the plasmatic P-selectin levels. Furthermore, in different clinical conditions, elevation of this marker may reflect endogenous platelet activation; however, optimal anticoagulant for blood collection is important for proper diagnostic valida tion.
Acquired Hemophilia A in Women Postpartum: Clinical Manifestations, Diagnosis, and Treatment
Authors: Michiels Jan Jacques
Published: November 2007

Acquired hemophilia A in women postpartum is diagnosed by a prolonged activated partial thromboplastin time (APTT), low plasma levels of coagulant factor VIII, and the detection of an inhibitor against factor VIII in the Bethesda assay. Effective treatment of bleeding symptoms should be based upon the clinical situation and depends on the inhibitor characteristics against human and porcine factor VIII. Immu nosuppression usually does not significantly affect the disap pearance of the factor VIII inhibitor antibody. The natural his tory of acquired hemophilia postpartum is independent of im munosuppressive treatment and featured by spontaneous disappearance of the inhibitor against factor VIII in the major ity of cases.
Simple and Safe Method to Prepare Patients With Prosthetic Heart Valves for Surgical Dental Procedures
Authors: Russo Giulia , Dal Corso Lorenza , Biasiolo Alessandra , Berengo Mario , Pengo Vittorio
Published: November 2007

Temporary discontinuation of high-intensity oral anticoagulant treatment is not recommended in patients under going dental surgery. This policy is not based on solid data from randomized clinical trials but on expert consensus. The alternative, i.e., to continue treatment and treat patients with tranexamic acid mouthwash, often is not applicable. A prospec tive cohort study was carried out to evaluate bleeding and thromboembolic complications in patients bearing prosthetic heart valves and registering International Normalized Ratio (INR) values between 2.0 and 4.5, who underwent dental pro cedures after a 2-day suspension of warfarin treatment. One hundred four consecutive patients receiving high-intensity an ticoagulation underwent 123 dental procedures after 2 days' warfarin withdrawal. No major bleeding complications oc curred in the week after the procedure; minor bleeding requir ing local measures occurred in two patients. No thromboem bolic events and no cases of bacterial endocarditis were re corded in the 3 months after the procedure. A mean decrease in INR by approximately 1.0 U (from 2.95 ± 0,59 to 1.87 ± 0,46) occurred after 2 days' warfarin suspension. Seven days after reinitiation of warfarin, INR values returned to the therapeutic range in 90% of cases. The calculated average time spent at INR less than 2.0 (critical value) was 28 hours. Two days' warfarin suspension is a simple and safe policy for patients with prosthetic heart valves undergoing dental surgery.
Sudden Cardiac Death From Thrombotic Thrombocytopenic Purpura
Authors: Wajima Takeshi , Johnson Edwin H.
Published: November 2007

Clinical thrombotic thrombocytopenic purpura (TTP) is characterized by a pentad of microangiopathic hemo lytic anemia, thrombocytopenia, neurological symptoms, renal involvement, and fever. A case of TTP in which early symp toms and signs were suggestive of ischemic heart disease, renal failure, and severe thrombocytopenia developed to a rapid out come of death. The postmortem examination revealed coronary artery microthrombi, typical of TTP. The clinical presentation of this TTP was atypical: severe thrombocytopenia, striking renal and CNS symptoms were present, but fever and anemia were not present. Thrombotic thrombocytopenic purpura is an uncommon condition that carries a high fatality rate if un treated. Awareness of this syndrome and its high risk of sudden death underlines the importance of rapid diagnosis and treat ment.
State-of-the-Art Review : Heparin-Induced Thrombocytopenia: A Critical Risk/Benefit Analysis of Patients in Intensive Care Treated With R-Hirudin
Authors: Schenk Joachim F. , Berg Gunter , Mörsdorf Stefan , Stefan Bernhard , Kroll Hartmut , Krischek Boris , Pindur Gerhard , Schieffer Herrmann , Wenzel Ernst
Published: November 2007

Patients in intensive care may be at high risk of in vivo platelet activation because comorbid conditions, such as infections, septicemia, shock, disseminated intravascular co agulation, and cancer represent procoagulant states. Hyperre activity of platelets with or without a decline of cell count may result in thromboembolic complications potentially associated with the phenomenon of heparin-induced thrombocytopenia. We analyzed the data of 10 patients highly suspected of having heparin-induced thrombocytopenia during their intensive care treatment of 29 plus or minus 22 days. In seven patients, throm bocytopenia coincided with thromboembolic complications. Six patients had additionally undergone fibrinolytic therapy before starting activated partial thromboplastin time-adapted alternative anticoagulation with r-hirudin. In three patients, the platelet count decreased without a clinical manifestation. of heparin-induced thrombocytopenia. R-Hirudin treatment moni tored by activated partial thromboplastin time and prothrombin time (PT) was effective and safe. The target value for activated partial thromboplastin time was a twofold prolongation. In four of five patients with deep venous thrombosis, a partial recana lization of the lower extremity could be achieved. Three pa tients with pulmonary embolism associated with deep venous thrombosis in two cases and in one additional case with an acute myocardial infarction did clinically profit from fibrino lysis with recombinant tissue plasminogen activator (rtPA) and r-hirudin treatment. Two lethal events probably caused by the underlying multimorbidity could not be prevented. No recur rence of thrombosis occurred, and there were no severe bleed ing complications attributed to r-hirudin treatment. Platelet counts were significantly reduced on day 9.4 plus or minus 6.4 of heparin administration in all cases (>50% decrease related to the initial values) from 224,000 plus or minus 126,000/μL to 96,000 plus or minus 61,000/μL, and increased during r- hirudin treatment to mean values of 224,000 plus or minus 126,000/μL. The heparin-induced platelet activation assay (HIPAA) assay was positive in 8/10 cases, whereas the PF4 enzyme-linked immunosorbent assay showed a positive result in four of eight analyzed cases. In four cases, the assays were concordantly positive. The PF4 enzyme-linked immunosorbent assay was not performed in two cases.
Ticlopidine, Alka-Seltzer®, or a Combination of Citric Acid With Aspirin: Effects on Platelet Aggregation in Individuals With an Insufficient Response to Aspirin Alone
Authors: Kaplan Svetlana , Kaplan Alexander , Marcoe Karen , Sauvage Lester R.
Published: November 2007

Aspirin (ASA) does not effectively lower platelet aggregation in all people. The platelet aggregation (PA) score is an easily used clinical method for measuring the effect in individuals of antiplatelet medications. Fifteen apparently healthy subjects (2 men and 13 women), selected for their resistance to ASA's antiaggregation effect, completed a se quential trial of ticlopidine, Alka-Seltzer®, and ASA + citric acid (CTA). Ticlopidine was the strongest aggregation inhibitor and the ASA + CTA combination was more inhibitory than Alka-Seltzer. It was determined that measuring antiaggregation effects of a particular agent in an individual prior to usage would optimize treatment. The PA score methodology provides a means for testing patients prior to antiplatelet therapy for prevention and treatment of the thrombotic complications of vascular disease.
arboxypeptidase U at the Interface Between Coagulation and Fibrinolysis
Authors: Schatteman Katinka , Goossens Filip , Leurs Judith , Verkerk Robert , Scharpé Simon , Michiels Jan J. , Hendriks Dirk
Published: November 2007

In 1988, Hendricks et al. first reported on the presence of carboxypeptidase U (U refers to the unstable nature of the enzyme) in human serum. One decade later, the importance of carboxypeptidase U (CPU) in the regulation of fibrin clot dissolution is well documented. CPU circulates in plasma as an inactive zymogen, proCPU, that is converted to its active form during coagulation and fibrinolysis. CPU cleaves off C-terminal lysine residues exposed on fibrin partially degraded by the action of plasmin. Because these C-terminal lysine residues are important for upregulating the fibrinolytic rate, CPU thus slows down fibrinolysis.
Acquired von Willebrand Syndrome in Systemic Lupus Erythematodes
Authors: Michiels Jan Jacques , Schroyens Wilfried , van der Planken Marc , Bememan Zwi
Published: November 2007

Acquired von Willebrand syndrome (AVWS) in systemic lupus erythematodes (SLE) is caused by autoantibodies directed against the circulating von Willebrand factor (vWF)/factor VIII (FVIII) complex. The autoantibody-vWF/ FVIII antigen complex is cleared rapidly from the circulation, leading to a moderate to severe quantitative and qualitative deficiency of both vWF and FVIIIc. Consequently, AvWS in SLE is featured by a prolonged bleeding time and normal platelet count, a prolonged activated partial thromboplastin time (APTT) and normal prothrombin time (PT), decreased or absent ristocetin-induced platelet aggregation (RIPA), and type II vWF deficiency on multimeric analysis of the vWF protein. Acquired von Wittebrand syndrome type II in SLE responds poorly to 1-desamino-8-D-arginine vasopressin (DDAVP) and FV III concentrate, but responds transiently well to high-dose gammaglobulin given intravenously. All reported cases of AvWS in SLE were cured by appropriate treatment of the underlying autoimmune disease with prednisone or immunosuppressifln.
Platelet and Leukocyte Deactivation After Intracoronary Stent Placement in Patients Receiving Combined Antiplatelet Therapy
Authors: Atalar Enver , Aytemir Kudret , Haznedaroğlu Ibrahim , Aksöyek Serdar , Övünç, Kenan , Kirazli Şerafettin , Ozmen Ferhan
Published: November 2007

Activated platelets and leukocytes have been demonstrated to play a role in the development of stent thrombosis, and coronary angioplasty has been shown to result in activation of platelets, leukocytes, and endothelial cells. We aimed to evaluate the effects of intraccrrdnary stent placement and aspirin plus ticlopidine treatment on platelets, leukocytes, and endothelial cells via observing the serial changes in the circulating soluble forms of adhesion molecules in 54 patients with coronary artery disease, who had elective coronary angioplasty ;and stent implantation for a single lesion of the left anterior descending artery. After stent placement, intravenous heparin infusion was administered only for 24 hours, and aspirin plus ticlopidine treatment was applied for 1 month. Venous blood samples were drawn before stent placement, and repeated 24 and 48 hours after the procedure. Patients were excluded if they had had recent cardiovascular events or any illness that might influence platelet, leukocyte, and endothelial cell function. The plasma level of sL-selectin was significantly decreased 48 hours after coronary stenting (636 ± 110 ng/mL vs 567 ± 93 ng/mL; P = 0.001, respectively). Likewise, the plasma level of sP-selectin was also decreased significantly 48 hours after the procedure (260 ± 61 ng/mL vs 233 ± 83 ng/mL. P = 0.01). The sE-selectin level was found to be significantly increased 24 hours (31 ± 9 ng/mL vs 39 ± 12 ng/mL, P = 0.0001) and 48hours(31 ± 9 ng/mL vs 4? ± 15 ng/mL, P = 0.001) after coronary stenting. The results of our study suggest that significant platelet and leukocyte deactivation take place in patients treated with combined antiplatelet therapy after stenting; endothelial cell activation also occurs during this treatment.
Homozygous Patients With the 20210 G to A Prothrombin Polymorphism Remain Often Asymptomatic in Spite of the Presence of Associated Risk Factors
Authors: Girolami Antonio , Scarano Luigi , Tormene Daniela , Cella Giuseppe
Published: November 2007

Patients who are homozygous for the G to A non-translated prothrombin polymorphism only occasionally have venous thrombosis. An evaluation of all published papers on the subjects has disclosed that nine patients of the 35 so far reported remained asymptomatic in spite of the presence of associated congenital or acquired thrombotic risk factors. We saw an additional patient recently, bringing the total to 10 of 36 patients. Some of these patients remained asymptomatic in spite of multiple or repetitive risk factors (e.g., five pregnancies in the case of one patient). Twelve patients who were homozygous and who had this polymorphism developed symptoms only in the presence of the same risk factors. This may suggest that this abnormality played a small role, if in both groups of patients. The finding that several patients with this abnormality remained asymptomatic in spite of associated risk factors casts serious doubts about the prothrombotic significance of this polymorphism. Until this problem is clarified, the Clinician must abstain from attributing a prothrombotic effect to this polymorphism.
Anticoagulant and Antiprotease Profiles of a Novel Natural Heparinomimetic Mannopentaose Phosphate Sulfate (PI-88)
Authors: Demir Muzaffer , Iqbal Omer , Hoppensteadt Debra A. , Piccolo Pietro , Ahmad Sarfraz , Schultz Christopher L. , Linhardt Robert J. , Fareed Jawed
Published: November 2007

Heparinomimetic mannopentaose phosphate sulfate (PI-88) (Progen Industries Ltd. Brisbane, Australia), currently developed as an anticoagulant and antiproliferative agent, mainly is composed of a pentomannan. However, tetrasaccharide and disaccharide components are also present. The molecular profile and the anticoagulant potency of PI-88 are investigated in this study. Gel permeation chromatography and polyacrylamide gel electrophoresis analyses were carried out to determine the molecular profile and separation of components of PI-88, respectively. Potentiation of antithrombin III (ATIII) and heparin cofactor-II (HC-11) activity were measured using chromogenic substrate assay. In order to determine anticoagulant and antiprcatease effects of PI-88, various global anticoagulant tests, such as the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), Hep-test@ (Haemachem Inc., St. Louis), ecarin clotting time (ECT), activated clotting time (ACT), and thromboelastography (TEG) were used. Anti-Xa and anti-IIa activities also were measured. The effect of PI-88 on the release of tissue factor pathway inhibitor (TFPI) was performed in nonhuman primates who received PI-88 and in endothelial cell culture systems. The relative susceptibility of PI-88 to heparinase 1, protamine sulfate (PS), and platelet factor 4 (PF4) also was evaluated. The high-performance liquid chromatography profiles of PI-88 showed that its average molecular weight is approximately 2300 Da. Separation and gradient electrophoretic . patterns of PI-88 showed that it is composed of five different fractions. This agent activates HC-II through inhibiting the thrombin generation but not inhibiting ATIII. Although PI-88 produced a concentration-dependent prolongation of all of the clotting tests, ECT gave the best correlation in the dose-response curve (ECT, r2 = 0.94; TT, r2 = 0.84; APTT, r2 = 0.69). Heparinomimetic mannopentaose phosphate sulfate (PI-88) exhibited marked inhibition of FIIa, but not of FXa. Heparinase I failed to produce significant neutralization of PI-88 in all the assays used, whereas PS and PF4 partially neutralized the effects of this compound. Heparinomimetic mannopentaose phosphate sulfate (PI-88) produced fivefold increase in the TFPI levels at 15 minutes after intravenous (IV) injection to primates. The incubation of PI-88 in endothelial cell culture system also showed a strong effect on TFPI release. These results suggest that PI-88 exhibited strong antithrombotic and anticoagulant activity in addition to its known antiproliferative properties. Because of the molecular characteristics and the dual nature of the pharmacokgic action of PI-88., this agent represents an attractive pharmacotogic agent for the control of thrombotic and proliflerative disorders.
Hemostatic and Fibrinolytic Status in Patients With Ovarian Cancer and Benign Ovarian Cysts: Could D-dimer and Antithrombin III Levels Be Included as Prognostic Markers for Survival Outcome?
Authors: Koh Stephen C.L. , Tham Kok-Fun , Razvi Khalil , Oei Pau-Ling , Lim Fang-Kan , Roy A.-C. , Prasad R.N.V.
Published: November 2007

We determined the hemostatic and fibrinolytic status in 60 patients with ovarian cancer and benign ovarian cysts. Hypercoagulation, increased platelets, and enhanced fibrinolysis were seen in patients with preoperative ovarian cancer compared to patients with benign ovarian cysts. Enhanced thrombin generation, evidenced by increased F1+2 and decreased antithrombin III (ATIII) levels with further enhanced fibrinolysis by elevated D-dimer, was seen in advanced cancer. Ten ovarian cancer patients died within 13 months after diagnosis and another died at 24 months, all from advanced stage of cancer, except one from stage IC cancer who died at 11. months. The survival rates from the disease at 13 months and 24 months were 66.7% and 45%, respectively. Most of the patients had gone through the complete course of chemotherapy, and those patients still alive have been disease free between 13 and 42 months. No statistical relationships for the hemostatic parameters studied in ovarian cancer patients could be found between those who died and those still living 13 and 24 months after diagnosis, except for ATIII and D-dimer levels.

Elevated D-dimer levels were associated with those who died within 13 and 24 months from the disease, and the decreased ATIII levels only reached statistical significance by 24 months. It could be suggested that these two parameters might be useful as systemic prognostic markers in survival outcome from the disease for the first 24 months in advanced ovarian cancer, in addition to the known correlation with the International Federation of Gynecology and Obstetrics stage. Key Words: Hemostatic—fibrinolytic—Ovarian cancer.
State-of-the-Art Review: Anticoagulation: The Present and Future
Authors: Van Aken Hugo , Bode Christoph , Darius Harald , Diehm Curt , Encke Albrecht , Gulba Dietrich C. , Haas Sylvia , Hacke Werner , Puhl Wolfhart , Quante Markus , Riess Hanno , Scharf Rüdiger , Schellong Sebastian , Schrör Karsten , Schulte Karl-Ludwig , Tebbe Ulrich
Published: November 2007

Thrombin is a central bioregulator of coagulation and is therefore a key target in the therapeutic prevention and treatment of thromboembolic disorders, including deep vein thrombosis and pulmonary embolism. The current mainstays of anticoagulation treatment are heparins, which are indirect hrombin inhibitors, and coumarins, such as warfarin, which modutate the synthesis of vitamin K-dependent proteins. Although efficacious and widely used, heparins and coumarins have limitations because their pharmacokinetics and anticoagulant effects are unpredictable, with the risk of bleeding and other complications resulting in the need for close monitoring with their use. Low-molecular-weight heparins (LMWHs) provide a more predictable anticoagulant response, but their use is limited by the need for subcutaneous administration. In addition, discontinuation of heparin treatment can result in a thrombotic rebound due to the inability of these compounds to inhibit clot-bound thrombin. Direct thrombin inhibitors (DTI) are able to target both free and clot-bound thrombin. The first to be used was hirudin, but DTIs with lower molecular weights, such as DuP 714, PPACK, and efegatran, have subsequently been developed, and these agents are better able to inhibit clot-bound thrombin and the thrombotic processes that take place at sites of arterial damage. Such compounds inhibit thrombin by covalently binding to it, but this can result in toxicity and nonspecific binding. The development of reversible noncovalent DTIs, such as inogatran and melagairan, has resulted in safer, more specific and predictable anticoagulant treatment. Oral DTIs, such as ximelagatran, are set to provide a further breakthrough in the prophylaxis and treatment of thrombosis.
Immobilized Thrombin Receptor Agonist Peptide Accelerates Wound Healing in Mice
Authors: Strukova Svetlana M. , Dugina Tamara N. , Chistov Ivan V. , Lange Maria , Markvicheva Elena A. , Kuptsova Svetlana , Zubov Vitaliy P. , Glusa Erika
Published: November 2007

To accelerate the healing processes in wound repair, attempts have been repeatedly made to use growth factors including thrombin and its peptide fragments. Unfortunately, the employment of thrombin is limited because of its high liability and pro-inflammatory actions at high concentrations. Some cellular effects of thrombin in wound healing are mediated by the activation of protease activated receptor-1 (PAR-1). The thrombin receptor agonist peptide (TRAP:SFLLRN) activates this receptor and mimics the effects of thrombin, but TRAP is a relatively weak agonist. We speculated that the encapsulated peptide may be more effective for PAR-1 activation than nonimmobilized peptide and developed a novel method for TRAP encapsulation in hydrogel films based on natural and synthetic polymers. The effects of an encapsulated TRAP in composite poly(N-vinyl caprolactam)-calcium alginate (PVCL) hydrogel films were investigated in a mouse model of wound healing. On day 7 the wound sizes decreased by about 60% under TRAP-chitosan-containing PVCL films, as compared with control films without TRAP. In the case of TRAP-polylysine-containing films no significant decrease in wound sizes was found. The fibroblast/macrophage ratio increased under TRAP-containing films on day 3 and on day 7. The number of proliferating fibroblasts increased to 150% under TRAP-chitosan films on day 7 as compared with control films. The number of [3H]-thymidine labeled endothelial and epithelial cells in granulation tissues was also enhanced. Thus, the immobilized TRAP to PVCL-chitosan hydrogel films were found to promote wound healing following the stimulation of fibroblast and epithelial cell proliferation and neovascularization. Furthermore, TRAP was shown to inhibit the secretion of the inflammatory mediator PAF from stimulated rat peritoneal mast cells due to augmentation of NO release from the mast cells. The encapsulated TRAP is suggested to accelerate wound healing due to the anti-inflammatory effects and earlier development of the proliferative phase of wound healing.
ProC Global: A New Automated Screening Assay for the Evaluation of Total Function of the Protein C System
Authors: Dragoni Francesco , Tormene Daniela , Simioni Paolo , Arcieri Paolo , Avvisati Giuseppe , Girolami Antonio
Published: November 2007

Protein C (PC) pathway represents a major physiologic inhibitory mechanism regulating the coagulation cascade. A new automated functional screening assay (ProC Global) for the evaluation of the PC-system was tested to define its ability to identify patients with known inherited defects such as factor V (FV) Leiden mutation and PC and protein S (PS) deficiency. A total of 249 patients who were symptomatic or asymptomatic for previous venous thromboembolism (VTE) were evaluated, 50 of whom had FV Leiden mutation, 36 had PC deficiency, and 34 had PS deficiency. One hundred healthy subjects were also tested, as well as 40 blood donors of both sexes in whom coagulation abnormalities were not found. Results of ProC Global test were expressed as normalized ratio (NR) and values below an established cut-off level were consistent with a positive test. ProC Global was positive in all 50 patients with the FV Leiden mutation (mean NR = 0.59; range, 0.37 to 0.69). ProC Global correctly identified 32 of 36 (89%) PC defects (mean NR = 0.63; range, 0.34 to 1.21) and 25 of 34 (73.5%) PS defects (mean NR = 0.76; range, 0.5 to 1.23). Overall, 92.5% of hereditary defects of the PC system considered in this study were identified by ProC Global test. ProC Global exhibited NR above cut-off level in all 40 blood donors without coagulation defects. ProC Global is a new automated screening test with some diagnostic potential in identifying patients with defects of the PC system. However, ProC Global in its current form cannot substitute the assay of each single component of this inhibitory system in the daily screening for thrombophilia.