Reduction In Thrombotic Events Research Articles

Anagrelide reduces thrombotic risk in essential thrombocythaemia vs. hydroxyurea plus aspirin.

To evaluate the reduction in thrombotic events (TE) in patients with essential thrombocythaemia (ET) treated with anagrelide versus hydroxyurea + aspirin (HU + ASA). A questionnaire was developed using 2008 WHO diagnostic criteria, and thrombotic risk factors were stratified according to Landolfi criteria. Through questionnaire completion, clinicians at Hungarian haematological centres entered data into the Hungarian MPN Registry on patients with myeloproliferative neoplasms. Based on ET registry data, TEs in anagrelide-treated patients (n = 139) were compared with HU + ASA-treated patients (n = 141). Patients were followed up for (median) 6 yr. TEs were reported in significantly fewer anagrelide-treated patients versus HU + ASA (15.1% versus 49.6%; P < 0.001). Numbers of major arterial and major venous events were similar between the groups, although there were over fivefold more minor arterial and minor venous events in the HU + ASA group (P < 0.001). While median age at diagnosis was older and length of follow-up shorter in the HU + ASA group (P < 0.05), this did not influence TE incidence; medication and TE before diagnosis only influenced TE incidence. Anagrelide significantly decreased the number of patients experiencing minor arterial and minor venous TEs versus HU + ASA over 6 yr. Risk of TE after diagnosis was significantly increased if the patient had TE before diagnosis.

Safety of glycoprotein IIb/IIIa inhibitors in patients under therapeutic hypothermia admitted for an acute coronary syndrome

BackgroundMild therapeutic hypothermia (MTH) is associated with an increased risk of both thrombotic and bleeding events. Although little is known about the use of Glycoprotein IIb-IIIa inhibitors (GPi) in this setting, the early action and the intravenous administration of these agents in patients who cannot swallow might potentially translate into clinical benefits in patients with acute coronary syndromes (ACS). AimsTo assess the incidence of bleeding/thrombotic events in patients with ACS under MTH after an Out-of-hospital cardiac arrest (OHCA) who received GPi or not. Methods and ResultsFrom January 2010 to September 2015, 110 patients were treated with MTH after an OHCA. Among them, 88 (80%) had an ACS and 71 patients (80.6%) underwent percutaneous coronary intervention (PCI). In 17 (24%) GPi were administered in the cath-lab. During hospitalization, 11.7% in the GPi and 9.25%in the non GPi group presented thrombotic events (stent thrombosis, deep vein thrombosis, pulmonary embolism) without significant differences between groups (p= 0.762). The incidence of any bleeding (64.7% vs. 14.8%; p<0.0001), and major bleeding (41.1% vs. 3.7; p<0.0001) was significantly higher in patients receiving GPi. Finally, in-hospital mortality did not differ between groups (24% vs. 35, 2%; p=0.385). ConclusionsIn this study, the use of GPi in patients with ACS undergoing PCI under MTH was associated with an increased bleeding risk without reduction of thrombotic events. According to these results, the use of GPi should be carefully considered in this setting.

Single vs Dual Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation: A Systematic Review.

There is wide variability in prescribing of antiplatelet regimens following transcatheter aortic valve implantation (TAVI). The objective of this review was to evaluate published and unpublished reports regarding the efficacy and safety of dual antiplatelet therapy (DAPT) compared with a single antiplatelet agent in patients undergoing TAVI. We searched MEDLINE, CENTRAL, Embase, and unpublished sources of literature from inception to December 2014 using terms synonymous with TAVI and DAPT. We included randomized controlled trials (RCTs) and cohort or case-control studies that compared DAPT with a single antiplatelet agent post-TAVI. Four articles met the inclusion criteria (2 RCTs, 2 cohort studies), of which all were deemed to be at high risk of bias, for a total of 662 patients. Compared with a single antiplatelet agent, DAPT did not significantly reduce all-cause mortality (risk ratio: 1.22, 95% confidence interval: 0.72-2.09, I(2) = 0%). Due to selective outcome reporting and variable follow-up, other outcomes of interest could not be meta-analyzed; however, evaluation of individual studies demonstrated no significant reduction in thrombotic events with DAPT and a similar or higher risk of bleeding. Current evidence, though limited by low methodological quality, suggests a lack of benefit and potential harm with DAPT compared with a single antiplatelet agent in patients post-TAVI. Therefore, clinicians should evaluate the use of DAPT in patients post-TAVI on a case-by-case basis until more robust evidence is available to guide practice.

Miejsce wystandaryzowanego ekstraktu z pomidorów w prewencji pierwotnej schorzeń układu sercowo-naczyniowego. Czy i kiedy stanowi alternatywę dla kwasu acetylosalicylowego? Stanowisko grupy ekspertów

Zastosowanie kwasu acetylosalicylowego (ASA) w prewencji pierwotnej schorzen ukladu sercowo-naczyniowego (CVD) poddano w wątpliwośc z powodu niezadawalającego stosunku korzyści do ryzyka takiego dzialania. Zastosowanie ASA w tym wskazaniu jest przedmiotem toczących sie debat. Doniesienia z piśmiennictwa wskazują na silne antyagregacyjne wlaściwości wystandaryzowanego ekstraktu z pomidorow (STE). Ekstrakt ten, pelniąc role zywności funkcjonalnej bądź suplementu diety, moglby dzieki swoim wlaściwościom antyagregacyjnym i przeciwzakrzepowym stac sie pomocny w prewencji pierwotnej zdarzen sercowo-naczyniowych (CV). Zanim zostaną zakonczone i opublikowane badania sluzące ustaleniu ostatecznego miejsca ASA w zapobieganiu incydentom CV, zaprezentowano dokument bedący stanowiskiem grupy ekspertow, w ktorym podsumowano mozliwe zastosowanie STE w prewencji pierwotnej CVD w wybranych populacjach osob doroslych.

Prognostic Impact of Clopidogrel Pretreatment in Patients With Acute Coronary Syndrome Managed Invasively

Pretreatment with antiP2Y12 agents before angiography in acute coronary syndrome (ACS) is associated with a reduction in thrombotic events. However, recent evidences have questioned the benefits of upstream antiP2Y12, reporting a higher incidence of bleeding. We analyzed the prognostic impact of clopidogrel pretreatment in a large cohort of invasively managed patients with ACS. In hospital, safety and efficacy of clopidogrel pretreatment were retrospectively analyzed in patients included in the ARIAM-Andalucía Registry (Analysis of Delay in Acute Myocardial Infarction). Propensity score and inverse probability of treatment weighting analysis were performed to control treatment selection bias. Results were stratified by ACS type. Sensitivity analyses were used to explore stability of the overall treatment effect. Of 9,621 patients managed invasively, 69% received clopidogrel before coronary angiography. In the ST-elevation myocardial infarction group, pretreatment was associated with a significant reduction in reinfarction (odds ratio 0.53, 95% confidence interval [CI] 0.27 to 0.96; p = 0.027), stent thrombosis (odds ratio 0.15, 95% CI 0.06 to 0.38; p <0.0001), and mortality (odds ratio 0.67, 95% CI 0.48 to 0.94; p = 0.020), with an increase in minor bleeding but remained as a net clinical benefit strategy. Those benefits were not present in patients without ST elevation (non-ST elevation ACS). The weighting and propensity analysis confirmed the same results. An interaction between pretreatment duration and bleeding was observed. In conclusion, pretreatment with clopidogrel reduced the occurrence of death and thrombotic outcomes at the cost of minor bleeding. Those benefits exclusively affected ST-elevation myocardial infarction cases. The potential benefit of routine upstream pretreatment in patients with non-ST-elevation ACS should be reappraised at the present.

Cangrelor: review of the drug and the CHAMPION programme (including PHOENIX).

Platelet inhibition is the main goal of ancillary pharmacologic therapy during percutaneous coronary interventions (PCI). Thienopyridines and ticagrelor are oral drugs developed for this purpose. Cangrelor is an intravenous, non-thienopyridine antagonist of the P2Y12 receptor with a rapid, potent, predictable, and quickly reversible effect. Cangrelor has been studied in a broad population intended to receive PCI in the CHAMPION program, where it was compared with different clopidogrel regimens. The first two trials, CHAMPION PCI and PLATFORM, failed their primary objective, likely for challenges in the adjudication of PCI-related myocardial infarction. In a third trial that implemented the universal definition of MI, CHAMPION PHOENIX, a reduction of thrombotic events, including stent thrombosis, was observed. In the BRIDGE trial cangrelor has been studied in patients who had to prematurely interrupt antiplatelet therapy for surgery. Cangrelor appears a promising agent in patients who require PCI or when a rapid reversal is needed.

Weight‐loss surgery rapidly alleviates platelet hyperactivity in morbid obesity

Morbid obesity is accompanied by platelet hyperactivity, leading to thrombotic events such as myocardial infarction and stroke. Platelets are pivotal for development of thrombosis. Bariatric surgery is the most effective intervention to reduce thrombotic events and alleviate type II diabetes in morbidly obese. However, effect of bariatric surgery on platelet function is largely unknown. In this pilot study we compared the short‐term effects of Roux‐en‐ Y Gastric Bypass (RY) and Lap Banding (LB) on prothrombotic monocyte‐platelet aggregates (MPA) that reflect platelet activation in vivo. MPA were measured in whole blood by flow cytometry pre‐ and post‐surgically at 1 and 3 months. In morbidly obese patients, MPA are drastically elevated compared to non‐obese controls. Both RY and LB decreased MPA in blood (unstimulated and stimulated with ADP). However RY alleviated platelet hyperactivity more rapidly (at 1 month post‐op) and more profoundly compared to LB. Bariatric surgery decreased MPA more profoundly in diabetics than in non‐diabetics. There is no correlation between BMI and decreased platelet activation after RY, but there is strong correlation after LB. Decreased MPA also correlates with decreased IL‐6 post‐surgically. Thus gastric bypass is more efficacious than gastric banding to reduce platelet hyperactivity in morbid obesity leading to a reduction in thrombotic events.

Antithrombotic outcome trials in acute coronary syndromes: seeking the optimal balance between safety and efficacy†

An intricate balance exists between the safety and efficacy of antithrombotic therapies in acute coronary syndrome (ACS). Safety is largely defined by bleeding risks. Many bleeding definitions are used in clinical trials, and conclusions may differ depending on the definition applied. Bleeding risks are typically dose related, making selection of the optimal dose (or preferably, doses) to advance from phase II to III testing a critical step in drug development.1 Efficacy is defined in terms of thrombotic event reduction and is commonly assessed using composite endpoints. However, composite endpoints create interpretive challenges within and across trials, particularly when endpoint definitions vary substantially. The trade-off between benefits (reduction in thrombotic events) and risks (increase in bleeding) is important to patients and clinicians; thus, it is imperative that data are presented clearly to facilitate informed decision making. Antithrombotic drug development for ACS is a challenging area of cardiovascular medicine, a topic discussed during the 7th and 8th Global Cardiovascular Clinical Trialists (CVCT) forums in December 2010 and 2011. This manuscript highlights key points from those discussions. Data from phase II trials are used to determine dose selection for phase III. However, it is not uncommon for phase II and III results to differ substantially ( Tables 1⇓–3 ). In the phase II studies of vorapaxar, prasugrel, and ticagrelor, there was no evidence of a statistically significant increase in bleeding when compared with standard therapy or placebo. However, in the larger phase III studies, an increased risk of bleeding not associated with coronary artery bypass graft (CABG) surgery was observed ( Tables 2 and 3 ). In the phase II studies of apixaban and rivaroxaban, dose-related increases in bleeding were observed leading to the selection of lower doses for phase III. Despite the dose reduction, bleeding was still higher with these drugs when …

Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data

Uptake of self-testing and self-management of oral anticoagulation [corrected] has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism. We searched Ovid versions of Embase (1980-2009) and Medline (1966-2009), limiting searches to randomised trials with a maximally sensitive strategy. We approached all authors of included trials and requested individual patient data: primary outcomes were time to death, first major haemorrhage, and first thromboembolic event. We did prespecified subgroup analyses according to age, type of control-group care (anticoagulation-clinic care vs primary care), self-testing alone versus self-management, and sex. We analysed patients with mechanical heart valves or atrial fibrillation separately. We used a random-effect model method to calculate pooled hazard ratios and did tests for interaction and heterogeneity, and calculated a time-specific number needed to treat. Of 1357 abstracts, we included 11 trials with data for 6417 participants and 12,800 person-years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0·51; 95% CI 0·31-0·85) but not for major haemorrhagic events (0·88, 0·74-1·06) or death (0·82, 0·62-1·09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0·33, 95% CI 0·17-0·66), as did participants with mechanical heart valve (0·52, 0·35-0·77). Analysis of major outcomes in the very elderly (age ≥85 years, n=99) showed no significant adverse effects of the intervention for all outcomes. Our analysis showed that self-monitoring and self-management of oral coagulation is a safe option for suitable patients of all ages. Patients should also be offered the option to self-manage their disease with suitable health-care support as back-up. UK National Institute for Health Research (NIHR) Technology Assessment Programme, UK NIHR National School for Primary Care Research.

Clopidogrel versus prasugrel in rabbits

The new P2Y(12) antagonist prasugrel produces greater inhibition of ADP-induced platelet aggregation (IPA) and reduction of thrombotic events in patients versus approved doses of clopidogrel, but increases major bleeding. We examined whether IPA level or P2Y(12) receptor occupancy (RO) could be optimized to better balance the efficacy and bleeding effects of these thienopyridines and reduce the response variability in rabbits. Rabbits were given three daily oral doses of clopidogrel (0.3-30 mg/kg/d), prasugrel (0.03-10 mg/kg/d) or vehicle (n = 6-40/group). Electrically-induced carotid artery thrombosis (AT, % thrombus weight reduction), cuticle bleeding time (BT, fold-increase over control), IPA to 20 microM ADP (% inhibition of peak light transmission) and RO (% inhibition of [(33)P]-2MeS-ADP binding to P2Y(1)-blocked platelets) were determined 2-3 hours after the last dose. ED(50) (doses for half-maximal effect, mg/kg/d) of AT, BT, IPA and RO were 1.6, 6.7, 1.9 and 1.4 for clopidogrel vs. 1.2, 1.9, 0.5 and 0.2 for prasugrel. IPA of 30-40% for both compounds produced the optimal balances of efficacy (AT: 50-60%) and BT of about 2-fold with significant RO of 70-80%. IPA of 50-60% achieved higher efficacy (AT: 60-80%), but with increased BT of five- to six-fold and >90% RO. Box-plot suggests no significant difference in the IPA and RO response variability between both compounds. Clopidogrel was 1.3-7 times less potent than prasugrel in rabbits, depending upon which biomarker was studied. The ratio of efficacy: bleeding was most favorable at a moderate IPA of 30% to 40%. Both compounds had similar IPA and RO response variability.

Eculizumab Therapy Results in Rapid and Sustained Decreases in Markers of Thrombin Generation and Inflammation in Patients with PNH

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a clonal disorder of the bone marrow resulting from an acquired mutation in the PIG-A gene. The mutation decreases production of the glycosylphosphatidylinositol membrane anchor for a variety of membrane proteins. Loss of cell membrane CD59 and CD55 results in enhanced complement-mediated cell membrane injury. PNH is associated with an increased risk of venous (VTE) and arterial thrombosis. Eculizumab, a monoclonal antibody to complement C5, has received FDA approval for the treatment of PNH. Recent published data demonstrates a 92% reduction in thrombotic events with the use of eculizumab. However, the mechanism for this reduction is unclear. We have enrolled eight PNH patients (pts) in an ongoing IRB-approved study on the effect of eculizumab treatment on markers of thrombin generation and inflammation. Patients were treated by the FDA-approved treatment protocol with blood samples obtained prior to treatment day 1 and prior to each dose on days 8, 15, 22, 29, 43 and 90. Patients receiving anticoagulants and corticosteroids were continued on their baseline medications. Plasma samples were assayed for D-dimers (D-D), thrombin-antithrombin complex (TAT), interleukin 6 (Il-6) by ELISA and tissue factor microparticles (TFMP) by impedance-based flow cytometry. Mean age of pts was 40.8 years (26–70); 6 male pts and 2 females. One patient had a prior history of VTE; 4 pts were receiving anticoagulants (1 full dose low molecular weight heparin (LMWH), 2 prophylactic LMWH, 1 warfarin) and 2 pts were receiving prednisone at the initiation of eculizumab. The effect of eculizumab on markers of hemostatic activation and inflammation was evaluated using Wilcoxon signed-rank test and multilevel models.Results: Pretreatment levels of D-D were significantly elevated in all but two of the patients who were receiving anticoagulants. Pretreatment Il-6 levels were significantly elevated in all but two patients taking prednisone. With eculizumab treatment, there was a statistically significant decrease in LDH (p=0.0001), D-D (p=0.0057), TAT (0.0138) and Il-6 (p=0.0362) during the 4 week induction phase of treatment (days 1–29). TAT levels significantly decreased by day 8 (p=0.008), with little subsequent change to day29 and day 90. All decreases in D-D, TAT, Il-6 and LDH were sustained in the maintenance phase of treatment (days29–90). Plasma TFMP were detectable and significantly increased in all patients prior to treatment. There was a statistically significant decrease in TFMP by day 8 (p=0.0234) and TFMP levels remained below pretreatment levels for the duration of the study (p=0.030). However, there were wide individual variations in TFMP levels over the course of treatment. There were significant Spearman correlations between changes in D-D and TAT (0.521; p<0.0001), in D-D and IL-6 (0.4400; p=0.0007). Changes in LDH did not correlate with changes in D-D, TAT, TFMP or Il-6. Changes in TFMP did not correlate with changes in markers of thrombin generation (TAT or D-D).Conclusion: Eculizumab treatment of patients with PNH results in a rapid decrease in plasma tissue factor microparticles, thrombin generation and inflammation. These changes appear to be independent of eculizumab suppression of RBC hemolysis as characterized by decreases in serum LDH. A direct relationship between plasma TFMP levels and thrombin generation in PNH patients could not be confirmed in this study. Taken together, these data indicate the broader impact of eculizumab treatment to suppress inflammation and prothrombotic activity in patients with PNH.

Mouse models of cystathionine β‐synthase deficiency reveal significant threshold effects of hyperhomocysteinemia

Untreated cystathionine beta-synthase (CBS) deficiency in humans is characterized by extremely elevated plasma total homocysteine (tHcy>200 microM), with thrombosis as the major cause of morbidity. Treatment with vitamins and diet leads to a dramatic reduction in thrombotic events, even though patients often still have severe elevations in tHcy (>80 microM). To understand the difference between extreme and severe hyperhomocysteinemia, we have examined two mouse models of CBS deficiency: Tg-hCBS Cbs(-/-) mice, with a mean serum tHcy of 169 microM, and Tg-I278T Cbs(-/-) mice, with a mean tHcy of 296 microM. Only Tg-I278T Cbs(-/-) animals exhibited strong biological phenotypes, including facial alopecia, osteoporosis, endoplasmic reticulum (ER) stress in the liver and kidney, and a 20% reduction in mean survival time. Metabolic profiling of serum and liver reveals that Tg-I278T Cbs(-/-) mice have significantly elevated levels of free oxidized homocysteine but not protein-bound homocysteine in serum and elevation of all forms of homocysteine and S-adenosylhomocysteine in the liver compared to Tg-hCBS Cbs(-/-) mice. RNA profiling of livers indicate that Tg-I278T Cbs(-/-) and Tg-hCBS Cbs(-/-) mice have unique gene signatures, with minimal overlap. Our results indicate that there is a clear pathogenic threshold effect for tHcy and bring into question the idea that mild elevations in tHcy are directly pathogenic.

Effects of tomato extract on platelet function: a double-blinded crossover study in healthy humans

Aqueous extracts from tomatoes display a range of antiplatelet activities in vitro. We previously showed that the active components also alter ex vivo platelet function in persons with a high response to ADP agonist. The objective was to evaluate the suitability of a tomato extract for use as a dietary supplement to prevent platelet activation. A randomized, double-blinded, placebo-controlled crossover study was conducted in 90 healthy human subjects selected for normal platelet function. Changes from baseline hemostatic function were measured 3 h after consumption of extract-enriched or control supplements. Significant reductions in ex vivo platelet aggregation induced by ADP and collagen were observed 3 h after supplementation with doses of tomato extract equivalent to 6 (6TE) and 2 (2TE) tomatoes [3 micromol ADP/L: 6TE (high dose), -21.3%; 2TE (low dose), -12.7%; P < 0.001; 7.5 micromol ADP/L: 6TE, -7.8%, 2TE, -7.6%; P < 0.001; 3 mg collagen/L: 6TE, -17.5%; 2TE, -14.6%; P = 0.007]. No significant effects were observed for control supplements. A dose response to tomato extract was found at low levels of platelet stimulation. Inhibition of platelet function was greatest in a subgroup with the highest plasma homocysteine (P < 0.05) and C-reactive protein concentrations (P < 0.001). As a functional food or dietary supplement, tomato extract may have a role in primary prevention of cardiovascular disease by reducing platelet activation, which could contribute to a reduction in thrombotic events.

Statins attenuate thrombin‐stimulated tissue factor expression on human endothelial cells through regulation of cJun

Statins decrease agonist-stimulated expression of the procoagulant protein tissue factor (TF) in human endothelial cells, but the signaling pathways affected by statins have not been clearly delineated. We previously showed that thrombin promotes the increased expression of TF on human endothelial cells through increased expression of cFos and increased phosphorylation of cJun, components of the AP1 transcription factor. When human endothelial cells were pretreated overnight with 1 μM fluvastatin or simvastatin, thrombin (2 U/ml) stimulation of TF expression was greatly attenuated. Statin pretreatment did not significantly affect the expression of cFos, but decreased the expression of cJun. Moreover, cJun activation by its upstream regulator c-Jun NH2-terminal kinase (JNK) was greatly attenuated. Thus, fluvastatin and simvastatin impede the expression of TF in human endothelial cells through regulation of the AP1 transcription factor component cJun: cJun expression is reduced and its activation is diminished due to the decreased activity of the stress-activated kinase JNK. These studies demonstrate that statins can serve as potent pharmacological inhibitors of the JNK/cJun pathway in a pleiotropic, non-cholesterol dependent manner. This, then, provides a novel mechanism for statin-mediated reduction in thrombotic events. This research was supported by an AHA grant.

Aprotinin Shows Both Hemostatic and Antithrombotic Effects During Off-Pump Coronary Artery Bypass Grafting

Hemostatic drugs are widely thought to be unnecessary and potentially detrimental in off-pump coronary artery bypass graft surgery (OPCABG), despite well-established use in on-pump surgery. In a randomized, prospective OPCABG trial, we assessed efficacy and safety of aprotinin through a comprehensive assessment of graft patency and hematologic function. Sixty patients were randomly assigned to full-dose aprotinin or placebo. Heparin was titrated to a kaolin-based activated clotting time of greater than 300 seconds. Exclusionary criteria included creatinine greater than 2 mg/dL, conversion to on-pump CABG, and preoperative GPIIb/IIIa inhibition. Hematologic assessments were obtained preoperatively, at the end of surgery, and on days 1 and 3: mean platelet volume, thrombin generation (prothrombin fragment 1.2 assay), and aspirin resistance using a modified thrombelastography, whole blood aggregometry, 11-dehydro-thromboxane B2 levels, and flow cytometry. Thrombotic events were defined as postoperative myocardial infarction by electrocardiography or elevated troponin I, clinical stroke by examination and head computed tomography, and bypass graft failure by multichannel computed tomography angiography on day 5. Aprotinin was associated with a significant reduction in intraoperative and postoperative blood loss compared with placebo but had no effect on transfusion rates. Patients treated with aprotinin had significantly fewer thrombotic events (3% versus 23%, p < 0.05, Fisher's exact test) and less postoperative aspirin resistance (20% versus 46%, respectively, p < 0.05, Fisher's exact test). Postoperative prothrombin fragment 1.2 level was reduced by aprotinin use. Aprotinin reduced perioperative bleeding after OPCABG. Preserved aspirin sensitivity in the aprotinin group may explain the observed reduction in thrombotic events and might be related to the suppression of perioperative and transmyocardial thrombin formation.

Direct Thrombin Inhibitors for Treatment of Heparin Induced Thrombocytopenia, Deep Vein Thrombosis and Atrial Fibrillation

Thrombin is a central enzyme in hemostasis, exerting potent procoagulant effects and activating platelets. Recently, several small molecule direct thrombin inhibitors (DTI's) with important clinical applications have been developed. Both lepirudin and argatroban are effective in treatment of heparin-induced thrombocytopenia resulting in rapid normalization of platelet counts and a reduction in thrombotic events. Because of differences in clearance mechanisms, argatroban is preferable in patients with renal insufficiency and lepirudin if there is hepatic impairment. DTI's have also been evaluated in treatment of venous thromboembolism. Small studies with recombinant hirudin have shown promise. Ximelagatran is a new DTI in late-stage clinical trials with advantages for treatment of venous thromboembolism including oral administration and fixed dosing, making it convenient for long-term treatment. A Phase III trial demonstrated that ximelagatran was superior to placebo for preventing recurrent thrombosis in patients who had undergone six months of standard anticoagulant therapy for venous thromboembolism. Another large trial compared ximelagatran to standard treatment with enoxaparin and warfarin for treatment of symptomatic deep vein thrombosis in a Phase III trial of 2,528 patients. The results showed that ximelagatran administered twice daily was as effective as standard treatment in preventing recurrence with no increase in bleeding complications. Ximelagatran has also been evaluated in two Phase III trials in patients with atrial fibrillation. The primary analysis of both showed that ximelagatran was non-inferior to warfarin for preventing stroke and other embolic events with no increase in bleeding complications. Unexpectedly, elevated serum transaminase levels were observed in 5-10% of patients receiving ximelagatran for over 1 month, and routine monitoring may be necessary. The introduction of DTIs represents an important advance in treatment of heparin-induced thrombocytopenia. The oral direct thrombin inhibitor, ximelagatran, shows promise in providing simplified, effective therapy for venous thromboembolism and atrial fibrillation.

Use of Crit‐Line Delta H Access Blood Flow in a Vascular Access Management Program to Decrease Episodes of Thrombosis and Increase URR

Substantial morbidity occurs within the hemodialysis population due to complications of vascular access, most frequently manifests as thrombotic events. An access management goal was the reduction of thrombotic events and associated morbidity. Intra‐dialytic vascular access blood flow (ABF) measurements using Crit‐Line Delta H ABF have been previously shown to provide objective and accurate access flow data and were our primary method of evaluating access function. A designated ‘access manager’ was assigned responsibility to track all issues related to vascular access. Each patient's ABF was measured monthly and the flow ‘trend’ was graphed using Crit‐Line Access Manager software. Additional data, including auscultation, cannulation difficulties, failing URR, and increased venous pressures were also recorded. These data and ABF trends were used to establish an angiography ‘hot list’. Following angioplasty, ABF was again measured to confirm a successful intervention. The ‘hot list’ led to 43 angiography referrals of which 83.7% (36/43) required subsequent intervention resulting in significant reductions of thrombosis events in PTFE grafts and native fistulae. The annual incidence of thrombotic events decreased from 1.6 to 0.4 events/patient year in grafts and 0.5–0.0 events in fistulae. Additionally, the percentage of URR's &gt; 70 increased from 82.3 to 90.1% over the same time period. Use of the Crit‐Line Delta H ABF device in conjunction with a vascular access management program can significantly reduce the number of thrombotic events per patient year.

Angiotensin II increases plasminogen activator inhibitor type 1 and tissue-type plasminogen activator messenger RNA in cultured rat aortic smooth muscle cells.

The role of angiotensin as a vasoconstrictor is well established. Lately, several other actions of this hormone on vascular smooth muscle (VSM) cells have been recognized including the induction of hypertrophy and/or DNA synthesis. Platelet-derived growth factor (PDGF), a mitogen recently shown to increase plasminogen activator inhibitor type 1 (PAI-1) synthesis in VSM cells, shares with angiotensin II (Ang II) several steps of its intracellular signaling pathway. The expression of PAI-1 and tissue-type plasminogen activator (TPA) mRNA in cultured rat VSM cells was studied. Northern blot analysis demonstrated a severalfold increase in the PAI-1 mRNA 3 to 8 hours after stimulation with 300 nmol/L Ang II. A similar response for TPA mRNA was observed. This induction did not require the synthesis of an intermediate protein or peptide because it was not affected by cycloheximide. In the cell-conditioned supernatant, the net result was an increase in PAI-1 activity from 4.18 +/- 1.8 to 13.2 +/- 6.8 IU/mL 6 hours after the addition of 300 nmol/L Ang II (mean +/- SD, P < or = .008, n = 6). The Ang II-induced increase in PAI activity was dose related, with a maximal effect at a concentration of 23 nmol/L (n = 3) and an ED50 of 3.3 +/- 1.5 nmol/L (n = 3). [Sar1-Ile8]angiotensin II, a specific competitive antagonist of Ang II, blocked 90 +/- 9% (n = 3) of the PAI activity induced by 10 nmol/L Ang II. In basal conditions, fibrin overlay zymography demonstrated the presence of free TPA. After stimulation with Ang II, lysis caused by the in situ dissociation of TPA was also present in the region of the TPA/PAI-1 complex. Angiotensin I (Ang I) elicited an increase in PAI activity similar to that obtained with equivalent doses of Ang II. Captopril (5 micrograms/mL), an inhibitor of the angiotensin-converting enzyme (ACE), completely prevented the Ang I effect, demonstrating that VSM cells display an ACE-like activity. Recent research has demonstrated the existence of a localized vascular renin-angiotensin system. The finding that Ang II can potentially modulate the plasminogen activation in the arterial wall has important biological and therapeutical implications for the evolution of arterial wall thrombi and the migration of cells through the vessel wall in the genesis of atherosclerotic lesions. We speculate that the reduction in thrombotic events observed in patients with a previous myocardial infarction and in high-renin, hypertensive patients treated with ACE inhibitors could be due at least in part to the decreased production of PAI-1 by VSM cells caused by these agents.