OBJECTIVE

The aim of this study was to identify a subset of patients at high risk of bleeding or myocardial infarction from a percutaneous coronary intervention and to investigate whether such high-risk subsets derive preferential benefit from heparin or bivalirudin.

RESULTS

This study included 4570 patients with coronary artery disease enrolled in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment trial and randomized to receive bivalirudin or heparin. Primary outcomes were in-hospital incidence of major bleeding and 30-day incidence of myocardial infarction. Major bleeding, myocardial infarction, and bleeding plus myocardial infarction occurred in 140, 204, and 34 patients, respectively. Older age, female sex, lower body weight, low cholesterol, multi-lesion intervention, complex lesions, and heparin therapy were independent correlates of increased risk of bleeding. Multi-lesion intervention, unstable angina, and lower body weight correlated independently with increased risks of myocardial infarction. Compared with heparin, bivalirudin was associated with a reduction in major bleeding (3.1 vs. 4.6%, P = 0.008), but mostly in low-risk patients. A reduction in the bleeding risk inversely correlated with an increase in the risk of myocardial infarction with bivalirudin (R = -0.61).

CONCLUSIONS

Bivalirudin and unfractionated heparin have a differential effect on risk of bleeding and myocardial infarction across various subsets of patients.

OBJECTIVE

Heparin-induced thrombocytopenia (HIT) is the most common form of drug-induced immune-mediated thrombocytopenia. HIT may be aggravated by life-threatening arterial and venous thrombosis and, to a lesser extent, hemorrhagic complications. We investigated the incidence of thromboembolic and hemorrhagic complications in critically ill patients with the multiple organ dysfunction syndrome and HIT.

METHODS

Case-control study.

METHODS

A 33-bed general intensive care unit in a university-affiliated teaching hospital.

METHODS

Twenty consecutive patients with laboratory-proven HIT compared with 20 contemporary, consecutive patients without HIT.

METHODS

Unfractionated heparin or low-molecular-weight heparin were replaced by danaparoid sodium in patients with HIT.

RESULTS

Heparin-induced thrombocytopenia was proven by a positive platelet aggregation test. The HIT group consisted of 14 males and 6 females aged 65.2+/-10.8 years (mean +/- standard deviation) with APACHE II scores of 26.7+/-5.4. Thrombocytopenia less than 100 x 10(9)/l developed within 6.4+/-7.0 days. In 12 patients thrombocytopenia resolved after discontinuation of unfractionated heparin in 8.8+/-6.4 days. Arterial and venous thromboembolic complications occurred more frequently in HIT patients than in non-HIT patients (10/20 (50%) versus 0/20 (0%); chi-square p<0.001). Hemorrhagic complications also occurred more frequently in HIT patients than in non-HIT patients (17/20 (85%) versus 7/20 (35%); chi-square p=0.001).

CONCLUSIONS

In critically ill patients with HIT, the incidence of thromboembolic complications and hemorrhagic complications was remarkably high.

BACKGROUND

Low-molecular-weight heparin (LMWH) is a popular alternative to unfractionated heparin (UH) for the treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), in part based on the perception of a lower risk for heparin-induced thrombocytopenia (HIT). To investigate the evidence supporting this perception, we performed a metaanalysis to compare the incidence of thrombocytopenia between LMWH and UH during PE and/or DVT treatment.

METHODS

Randomized trials comparing LMWH with UH for PE and/or DVT treatment were searched for in the MEDLINE database, bibliographies, and by correspondence with published investigators. Two reviewers independently selected high-quality studies and extracted data regarding heparin-associated thrombocytopenia (HAT), HIT confirmed by laboratory testing, and heparin-induced thrombocytopenia with thrombosis (HITT). Outcome rates between LMWH and UH were compared using a binomial, generalized linear mixed model with a logit link and Gaussian random effects for study.

RESULTS

Thirteen studies involving 5,275 patients met inclusion criteria. There were no statistically significant differences in HAT rates between the two treatments (LMWH, 1.2%; UH, 1.5%; p = 0.246). The incidence of documented HIT and HITT was too low to make an adequate comparison between groups.

CONCLUSIONS

Our review disclosed no statistically significant difference in HAT between LMWH and UH and insufficient evidence to conclude that HIT and HITT rates were different between them. There was no evidence from randomized comparative trials to support the contention that patients receiving treatment for PE or DVT with UH are more prone to these complications than those receiving LMWH.

Acute myocardial infarction (AMI) is infrequent in patients with idiopathic thrombocytopenic purpura (ITP) so the best treatment is not well known. The next case shows a 37-year-old man with chronic ITP who suffered an anterior AMI, the platelet count at admission was 39,000 microL. He was treated successfully with primary percutaneous angioplasty under anticoagulation with unfractionated heparin and antiaggregation with clopidogrel and ASA. At the end of the procedure we sealed the femoral access site with Angio-Seal(R). He didn t have any complications during the procedure and after six months remained asymptomatic. In some patients with chronic ITP and AMI the percutaneous treatment could be a good option.

BACKGROUND

Current treatment strategies for percutaneous coronary revascularization and acute coronary syndromes incorporate thrombin inhibition with either unfractionated or fractionated heparin. The peptide bivalirudin (Hirulog) is a direct thrombin inhibitor whose pharmacological properties differ from those of heparin. We conducted a systematic overview (meta-analysis) to assess the effect of bivalirudin on 4 end points: death, myocardial infarction, major hemorrhage, and the composite of death or infarction.

RESULTS

Six trials (5674 patients) represent the randomized, controlled bivalirudin experience, including 4603 patients undergoing elective percutaneous coronary revascularization and 1071 patients with acute coronary syndromes. ORs for the 4 clinical end points were calculated for each trial. Four trials (4973 patients) that compared bivalirudin with heparin were combined with the use of a random-effects model. In these trials, bivalirudin was associated with a significant reduction in the composite of death or infarction (OR 0.73, 95% CI 0.57 to 0.95; P=0.02) at 30 to 50 days, or 14 fewer events per 1000 patients so treated. There also was a significant reduction in major hemorrhage for the same trials (OR 0.41, 95% CI 0. 32 to 0.52; P<0.001, or 58 fewer events per 1000 patients so treated). A similar analysis combined 2 dose-ranging trials (701 patients) that compared therapeutic (activated partial thromboplastin time more than twice the control time) with subtherapeutic bivalirudin anticoagulation (activated partial thromboplastin time less than twice the control time).

CONCLUSIONS

Bivalirudin is at least as effective as heparin, with clearly superior safety. Thus, it provides an unprecedented net clinical benefit over heparin in patients with ischemic heart disease.

OBJECTIVE

To compare the feasibility and safety of transoesophageal echocardiograpy-guided cardioversion (CV) with enoxaparin and unfractionated heparin (UFH) in patients with atrial fibrillation (AF).

RESULTS

The Assessment of Cardioversion Using Transoesophageal Echocardiography (ACUTE) II pilot trial compared the safety and efficacy of enoxaparin with UFH in 155 patients with AF who were scheduled for transoesophageal echocardiography (TEE)-guided CV. Safety outcomes over a 5-week period were ischaemic stroke, major or minor bleeding, and death. Efficacy outcomes were length of stay (LOS) and return to normal sinus rhythm (NSR). Of the 76 patients assigned to the enoxaparin group, 72 (94.7%) had a transoesophageal echocardiogram and 63 (82.9%) had early CV, of which 59 (93.7%) were successful. Of the 79 UFH patients, 66 (83.5%) had a transoesophageal echocardiogram and 58 (73.4%) had early CV, of which 54 (98.2%) were successful. There were no significant differences in embolic events, bleeding, or deaths between groups. The enoxaparin group had shorter median LOS compared with the UFH group [3(2-4) vs. 4(3-5)] days; P<0.0001). There was also more NSR at 5 weeks in the enoxaparin group (76 vs. 57%; P=0.013).

CONCLUSIONS

In the ACUTE II trial, there were no differences in safety outcomes between the two strategies. However, the enoxaparin group had a shorter LOS. Thus, the TEE-guided enoxaparin strategy may be considered a safe and effective alternative strategy for AF. The shorter LOS may translate to lower costs using the enoxaparin TEE-guided approach.

Women with non-ST-elevation acute coronary syndrome are at increased risk for ischemic and bleeding complications compared with men. We examined the impact of gender and antithrombotic therapy for non-ST-elevation acute coronary syndrome on outcomes in patients in the ACUITY trial. Patients were randomized to heparin (unfractionated or enoxaparin) plus a glycoprotein IIb/IIIa inhibitor (GPI), bivalirudin plus a GPI, or bivalirudin alone. We compared major bleeding unconnected to coronary artery bypass grafting, composite ischemia (death, myocardial infarction, or revascularization), and net clinical outcome (composite ischemia or bleeding) in (1) men versus women overall and undergoing percutaneous coronary intervention (PCI) and (2) women overall and undergoing PCI by antithrombotic strategy. Of 13,819 patients enrolled, 4,157 were women (30.1%). Women had similar 30-day composite ischemia (7% vs 8%, p = 0.07) but greater 30-day rates of major bleeding (8% vs 3% p <0.0001) and net clinical outcomes (13% vs 10% p <0.0001) than men. One-year composite ischemia and mortality was similar. In women, bivalirudin compared with heparin + GPI resulted in less 30-day major bleeding (5% vs 10%, p <0.0001) but similar composite ischemia (7% vs 6%, p = 0.15). No differences were observed in rates of 1-year composite ischemia or mortality in women who received bivalirudin versus heparin + GPI. Results were similar in women undergoing PCI. In conclusion, women had similar 30-day mortality and composite ischemia but higher net clinical adverse events due to more bleeding complications than men; 1-year mortality was similar for men and women. In women, bivalirudin monotherapy compared with a GPI-based strategy resulted in significantly decreased bleeding but similar rates of 1-year composite ischemia and mortality.

BACKGROUND

Bivalirudin is a short-acting direct thrombin inhibitor, with advantages over unfractionated heparin for anticoagulation in cardiac surgery. We hypothesized that bivalirudin is not associated with a clinically important increase in blood loss compared with heparin with protamine reversal in patients undergoing off pump coronary artery bypass (OPCAB) surgery. We also assessed flow with angiography at 3 months using a modified Thombolysis in Myocardial Infarction (TIMI) grade in the grafted coronary arteries.

METHODS

One hundred patients were randomly assigned to receive bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/h infusion) or heparin (150 to 300 U/kg bolus) with protamine reversal.

RESULTS

A median of 3 (range, 1 to 5) grafts were inserted per patient. Blood loss for the 12 hours after study drug initiation in the bivalirudin group (median, 793 mL; interquartile range, 532 to 1,214 mL; range, 320 to 4,909 mL; n = 50) was not significantly greater than in the heparin group (median, 805 mL; interquartile range, 517 to 1,117 mL; range, 201 to 2,567 mL; n = 50; p = 0.165). Median graft flow was 3.0 in the bivalirudin group (n = 40) and 2.67 in the heparin group (n = 39; p = 0.047). The bivalirudin group had more patients with grade 3 (ie, full) flow in at least 1 graft (100% versus 90%; p = 0.04), a trend toward more patients with grade 3 flow in all grafts (60% versus 38%; p = 0.06), and more grafts with grade 3 flow (82% versus 67%; p = 0.03).

CONCLUSIONS

Anticoagulation for OPCAB surgery with bivalirudin was feasible without a clinically important increase in perioperative blood loss. Graft flow was better in the bivalirudin patients; the impact of this on clinical outcomes requires a larger study.

OBJECTIVE

To identify clinically important risk factors associated with upper extremity venous thrombosis following peripherally inserted central venous catheters (PICC).

METHODS

A retrospective case control study of 400 consecutive patients with and without upper extremity venous thrombosis post-PICC insertion was performed. Patient data included demographics, body mass index (BMI), ethnicity, site of insertion, size and lumen of catheter, internal length, infusate, and co-morbidities, such as diabetes mellitus, congestive heart failure, and renal failure. Additional risk factors analyzed were active cancer, any history of cancer, recent trauma, smoking, a history of prior deep vein thrombosis, and recent surgery, defined as surgery within three months prior to PICC insertion.

RESULTS

The prevalence of trauma, renal failure, and infusion with antibiotics and total parenteral nutrition (TPN) was higher among patients exhibiting upper extremity venous thrombosis (UEVT), when compared to controls. Patients developing UEVT were also more likely to have PICC line placement in a basilic vein and less likely to have brachial vein placement (P<.001). Left-sided PICC line sites also posed a greater risk (P=.026). The rate of standard DVT prophylaxis with low molecular weight heparin and unfractionated heparin and the use of warfarin was similar in both groups. Average length of hospital stay was almost double among patients developing UEVT, 19.5 days, when compared to patients undergoing PICC line insertion without thrombosis, 10.8 days (t=6.98, P<.001).

CONCLUSIONS

In multivariate analysis, trauma, renal failure, left-sided catheters, basilic placement, TPN, and infusion with antibiotics, specifically vancomycin, were significant risk factors for UEVT associated with PICC insertion. Prophylaxis with low molecular weight heparin, unfractionated heparin or use of warfarin did not prevent the development of venous thrombosis in patients with PICCs. Length of hospital stay and cost are markedly increased in patients who develop PICC-associated upper extremity venous thrombosis.

OBJECTIVE

To evaluate the effectiveness and the safety of danaparoid sodium in the treatment of critically ill patients with standard unfractionated heparin-induced thrombocytopenia (HIT) or low-molecular-weight HIT.

METHODS

University hospital.

METHODS

Retrospective analysis of 42 consecutive critically ill patients who were admitted for HIT between October 1992 and February 1997 and were treated either with therapeutic or prophylactic doses of danaparoid sodium.

RESULTS

Among the 26 patients treated with therapeutic doses, neither new thrombotic complications nor thrombosis extension was clinically suspected. Two deaths were directly related to lower limb acute arterial thrombosis associated with HIT. Two major hemorrhagic complications were observed when aspirin in addition to danaparoid sodium was administered. When danaparoid sodium was used in prophylactic doses (20 courses of treatment) to prevent either postsurgical or medical thrombotic complications, no thrombotic event was observed. No death related to HIT or danaparoid sodium treatment was observed. One aggravation of a postsurgical cerebral lesion was observed. During danaparoid sodium treatment, a persistence or a recurrence of thrombocytopenia was observed in 6.5% of patients without thrombotic complications.

CONCLUSIONS

Danaparoid sodium appears to be an efficient and safe treatment in critically ill patients with HIT. The concomitant use of aspirin in addition to danaparoid sodium seems to represent an important additional hemorrhagic risk that should be avoided in patient management.

OBJECTIVE

The aims of the Safety and Efficacy of Subcutaneous Enoxaparin Versus Intravenous Unfractionated Heparin and Tirofiban Versus Placebo in the Treatment of Acute ST-Segment Elevation Myocardial Infarction Patients Ineligible for Reperfusion (TETAMI) study were to demonstrate that enoxaparin was superior to unfractionated heparin (UFH) and that tirofiban was better than placebo in patients with acute ST-segment elevation myocardial infarction (STEMI) who do not receive timely reperfusion.

BACKGROUND

An optimal treatment strategy has not been identified for the many STEMI patients ineligible for acute reperfusion.

METHODS

A total of 1224 patients were enrolled in 91 centers in 14 countries between July 1999 and July 2002. Patients with STEMI ineligible for reperfusion were randomized to enoxaparin, enoxaparin plus tirofiban, UFH, or UFH plus tirofiban. All patients received oral aspirin. The primary efficacy end point was the 30-day combined incidence of death, reinfarction, or recurrent angina; the primary analysis was the comparison of the pooled enoxaparin and UFH groups.

RESULTS

The incidence of the primary efficacy end point was 15.7% enoxaparin versus 17.3% for UFH (odds ratio 0.89 [95% confidence interval CI = 0.66 to 1.21]) and 16.6% for tirofiban versus 16.4% for placebo (odds ratio 1.02 [95% CI 0.75 to 1.38]). The Thrombolysis In Myocardial Infarction (TIMI) major hemorrhage rate was 1.5% for enoxaparin versus 1.3% for UFH (odds ratio 1.16 [95% CI 0.44 to 3.02]) and 1.8% versus 1% for tirofiban versus placebo (odds ratio 1.82 [95% CI 0.67 to 4.95]).

CONCLUSIONS

This study did not show that enoxaparin significantly reduced the 30-day incidence of death, reinfarction, and recurrent angina compared with UFH in non-reperfused STEMI patients. However, enoxaparin appears to have a similar safety and efficacy profile to UFH and may be an alternative treatment. Additional therapy with tirofiban did not appear beneficial.

OBJECTIVE

To determine the cost effectiveness of enoxaparin therapy versus unfractionated heparin (UFH) therapy for patients with unstable coronary artery disease from the perspective of a Canadian hospital.

METHODS

A predictive decision analysis model using published clinical and economic evaluations and costs of medical care in Canada.

METHODS

A hypothetical cohort of patients presenting to hospital with unstable angina or non-Q-wave myocardial infarction as defined by the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) trial.

METHODS

Two antithrombotic treatment strategies were compared: (i) enoxaparin 1 mg/kg subcutaneously every 12 hours, and (ii) UFH intravenous bolus and constant infusion adjusted to maintain a therapeutic activated partial thromboplastin time. Both treatment strategies included 100 to 325 mg of oral aspirin daily. Enoxaparin or UFH was continued for a minimum of 48 hours to a maximum of 8 days. Cumulative outcomes were considered up to 30 days after initial presentation to hospital.

RESULTS

At 30 days, 19.8% of patients who received enoxaparin compared with 23.3% of patients who received UFH reached one of the primary composite events. There was no difference in major bleeding between the 2 treatment groups (6.5% enoxaparin vs 6.8% UFH). The average total direct medical cost per patient was $Can848 with the enoxaparin strategy versus $Can892 with the UFH strategy (1999 values). Therapy with enoxaparin was, therefore, considered to be the dominant strategy. Univariate sensitivity analysis indicated that the decision model was not robust to changes in the 30-day composite end-point, probability of recurrent angina, or base costs for treatment of recurrent angina or enoxaparin therapy.

CONCLUSIONS

Enoxaparin is the dominant antithrombotic pharmacotherapeutic strategy for patients with unstable coronary artery disease.

OBJECTIVE

The ISAR-REACT 4 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment-4) platelet substudy aimed to determine the relevance of high on-clopidogrel treatment platelet reactivity (HPR) in non-ST-segment elevation myocardial infarction patients that received abciximab with unfractionated heparin (UFH) or bivalirudin during percutaneous coronary intervention (PCI).

BACKGROUND

In patients undergoing PCI, HPR has been linked to a higher risk for ischemic events. The influence of HPR on clinical outcomes may differ with regard to the adjunctive antithrombotic treatment administered. In ISAR-REACT 4, bivalirudin treatment showed similar efficacy profiles as compared to abciximab with UFH. The impact of HPR on clinical outcomes in abciximab with UFH versus bivalirudin treated non-ST-segment elevation myocardial infarction patients has never been investigated specifically.

METHODS

A total of 564 patients (274 in abciximab/UFH group vs. 290 in bivalirudin group) were enrolled in this study. Presence or absence of HPR following clopidogrel loading was determined by platelet function testing on a Multiplate analyzer (Verum Diagnostica, Munich, Germany). Per study group and stratified in HPR and no-HPR patients, the 30-day incidence of a combined efficacy endpoint (death, myocardial infarction, urgent target vessel revascularization) was determined.

RESULTS

For abciximab with UFH, the incidence of the efficacy endpoint was similar in HPR versus no-HPR patients (9.4% vs. 6.7%; odds ratio: 1.4; 95% confidence interval: 0.6 to 3.5; p = 0.43). For bivalirudin, the incidence of the efficacy endpoint was significantly higher in HPR versus no-HPR patients (22.0% vs. 5.0%; odds ratio: 5.4; 95% confidence interval: 2.4 to 12.1; p < 0.0001).

CONCLUSIONS

For patients with a risk profile similar to the subjects enrolled in this platelet substudy, the impact of HPR on clinical outcomes may depend on the type of adjunctive antithrombotic therapy used during PCI. Further investigations are warranted to clarify whether assessment of platelet function may help tailoring antithrombotic therapy during PCI.

Venous thromboembolism (VTE) is one of the most relevant causes of maternal death in industrialized countries. Low molecular weight heparin (LMWH), continued throughout the entire pregnancy and puerperium, is currently the preferred treatment for patients with acute VTE occurring during pregnancy. However, information on the efficacy and safety of anticoagulant drugs in this setting is extremely limited. We carried out a systematic review and a meta-analysis of the literature to provide an estimate of the risk of bleeding complications and VTE recurrence in patients with acute VTE during pregnancy treated with antithrombotic therapy. The weight mean incidence (WMI) of bleeding and thromboembolic events and the corresponding 95% confidence interval (CI) were calculated. Eighteen studies, giving a total of 981 pregnant patients with acute VTE, were included. LMWH was prescribed to 822 patients; the remainder were treated with unfractionated heparin. Anticoagulant therapy was associated with WMIs of major bleeding of 1.41% (95% CI 0.60-2.41%; I) antenatally and 1.90% (95% CI 0.80-3.60%) during the first 24 h after delivery. The estimated WMI of recurrent VTE during pregnancy was 1.97% (95% CI 0.88-3.49%; I(2) 39.5%). Anticoagulant therapy appears to be safe and effective for the treatment of pregnancy-related VTE, but the optimal dosing regimens remain uncertain.

OBJECTIVE

We sought to evaluate international patterns of use and factors influencing use of evidence-based medications early after ACS.

RESULTS

Using a database of 15904 ACS patients enrolled in the SYMPHONY and 2nd SYMPHONY trials in 37 countries, we performed descriptive and logistic regression analyses. After controlling for other factors, region was significantly associated with the use of every class of evidence-based medication, most pronounced for intravenous unfractionated heparin (IV UFH), low-molecular-weight heparin (LMWH), angiotensin II converting enzyme inhibitors (ACEI) and discharge use of lipid-lowering agents. Latin America and Eastern Europe were among the highest users of early ACEI, yet the lowest users of discharge lipid-lowering therapy. Relative to the United States, all regions except Canada had greater use of LMWH and lower use of IV UFH. Compared with patients with acute myocardial infarction, those with unstable angina less often received aspirin, beta-blockers, ACEI, or IV UFH. Older age was associated with lower use of aspirin, beta-blockers, IV UFH, and lipid-lowering agents.

CONCLUSIONS

Use of evidence-based therapies for management of ACS patients is strongly associated with region. To improve patient outcomes, more research is needed to understand this variation, and to institute appropriate solutions.

OBJECTIVE

To determine the effects of age on outcomes in patients with STEMI treated with a strategy of enoxaparin (ENOX) vs. unfractionated heparin (UFH).

RESULTS

In the ExTRACT-TIMI 25 trial, 20,479 patients with STEMI were randomized in a double-blind fashion to UFH or ENOX. A novel reduced dose of ENOX was administered to patients>>or=75 years, and a reduced dose in those with an estimated creatinine clearance of < 30 mL/min. Anti-Xa levels were measured in a subset of patients (n = 73). The exposure to anti-Xa over time was lower in the elderly (AUC(0-12 h) P < 0.0001; AUC(steady-state) P = 0.0046). The relative risk reduction (RR) with ENOX on the primary endpoint, i.e. death or non-fatal recurrent myocardial infarction, was greater in patients < 75 years (20%) than>> 75 years (6%), but the absolute benefits were similar. When compared with UFH, ENOX was associated with an RR of 1.67 for major bleeding, but the magnitude of the excess risk tended to be lower (RR = 1.15) in patients>>or= 75 years assigned to ENOX.

CONCLUSIONS

A dose reduction of ENOX in the elderly appears to be helpful in ameliorating bleeding risk. A strategy of ENOX was superior to UFH in both young and elderly patients with STEMI treated with fibrinolysis.

The distribution of sites with high affinity for antithrombin III in [35S]heparin proteoglycans from rat skin was studied by affinity chromatography of the intact proteoglycans (Mr congruent to 1 x 10(6)) and degradation products. Unfractionated proteoglycan and proteoglycan fractions with low affinity and high affinity separated on antithrombin III-agarose were treated with alkali, releasing heparin chains (Mr congruent to 1 x 10(5)). Each chain preparation was fractionated on antithrombin III-agarose into fractions with low affinity and high affinity. Unfractionated proteoglycan and proteoglycan fractions with low affinity and high affinity were incubated with rat serum at pH 6.0, which gave products of similar size to commercial heparins (Mr congruent to 1 x 10(4)) termed heparin fragments. Each fragment preparation was fractionated on antithrombin III-agarose, yielding fractions with no affinity, low affinity, and high affinity, 40% of the proteoglycan preparation had low affinity, containing 4% high affinity chains and 7% high affinity fragments. The high affinity proteoglycan fraction yielded 40% high affinity chains and 22% high affinity fragments. The data show that the distribution of binding sites with high affinity for antithrombin III in heparin proteoglycans is highly asymmetric. Therefore, the concept that polymer modification reactions occurring during heparin biosynthesis, which must be involved in the formation of high affinity binding sites, occur in a random way must be reappraised.

BACKGROUND

The present study was undertaken to compare the role of aspirin versus aspirin plus heparin combination in pregnant women with poor obstetric history and raised anticardiolipin antibodies IgG (IgG(acl)).

METHODS

The study was conducted on 550 pregnant women, 450 with a history of two or more spontaneous abortions forming the study group, while 100 women with one or more live births and no history of abortion were controls. Their blood was tested to assess the level of IgG(acl) by enzyme-linked immunosorbent assay (ELISA). The test was strongly positive in 72 (16%) patients of the study group, who were randomized to receive either low-dose aspirin (80 mg/day) or a combination of low-dose aspirin (80 mg/day) and 5000 IU of unfractionated heparin subcutaneously 12 hourly under hospital surveillance. The pregnancy outcomes were statistically compared.

RESULTS

Of the 39 patients treated with low-dose aspirin, 24 (61.5%) gave birth to live issues compared with 28 (84.8%) of the 33 women given a combination of aspirin and heparin (p<0.05), an overall success rate of 72.2%. Mean birth weight of the babies given treatment with heparin and aspirin was 3.21+/-0.33 kg compared with 2.77+/-0.14 kg achieved with aspirin alone (p<0.001). Both treatments were well tolerated.

CONCLUSIONS

The study provides evidence that in cases of recurrent abortions with raised IgG(acl), treatment with a combination of aspirin and heparin showed better outcome than treatment with aspirin alone.

OBJECTIVE

We compared adherence to unfractionated heparin (UFH) 2 or 3 times daily prophylaxis orders versus low-molecular-weight heparin (LMWH) once daily orders. Our goals were to determine which strategy demonstrated the best adherence in terms of timing and frequency of dose administration, and to determine reasons for ordered heparin not being administered.

METHODS

We queried our electronic medication administration record where nurses document reasons for delayed administration or omitted doses. We identified 250 consecutive patients who were prescribed prophylaxis with UFH 2 or 3 times daily or LMWH once daily. We followed patients for their hospitalization to determine adherence to physicians' prophylaxis orders.

RESULTS

Adherence, defined as the ratio of prophylaxis doses given to doses ordered, was greater with LMWH (94.9%) than UFH 3 times daily (87.8%) or UFH twice daily (86.8%) regimens (P <.001). Patients receiving LMWH more often received all of their scheduled prophylaxis doses (77%) versus UFH 3 times daily (54%) or UFH twice daily (45%) (P <.001). There were no differences between regimens regarding reasons for omitted doses. The most common reason for late or omitted doses was patient refusal, which explained 44% of the UFH and 39% of the LMWH orders that were not administered.

CONCLUSIONS

LMWH once a day had better adherence than UFH 2 or 3 times daily. For both LMWH and UFH, patient refusal was the most common reason for not administering prophylaxis as prescribed. These findings require consideration when evaluating pharmacological prophylaxis strategies. Educational programs, explaining the rationale, may motivate patients to improve adherence during hospitalization.

The binding of glycosaminoglycans to intact washed human platelets was studied. The platelet binding of a 3H-labeled unfractionated heparin was saturable and reached equilibrium in 10-15 minutes. Heparin binding was specific: a 50-fold molar excess of an equivalent unlabeled heparin displaced up to 90% of labeled heparin, while chondroitin sulfate A and hyaluronic acid minimally displaced the binding of labeled heparin. Low molecular weight heparin fragments showed intermediate efficacy in displacing the binding of unfractionated [3H]heparin. Dextran sulfate (Mr 8,000, sulfation 17%) was as potent as unfractionated heparin in displacing binding, while neutral dextrans were ineffective. We observed that platelet activation by the calcium ionophore A23187 increased heparin binding by 2 to 3-fold, principally by enhancement of binding capacity not binding affinity. This process of heparin binding to the platelet surface may mediate some of the reported effects of heparin on platelet behavior.

A high-resolution online reverse-phase-high-performance liquid chromatography (RP-HPLC)-fluorescence detector (Fd)-electrospray ionization-mass spectrometry (ESI-MS) separation and structural characterization of disaccharides prepared from heparin (Hep), heparan sulfate (HS), and various low-molecular-weight (LMW)-Hep using heparin lyases and derivatization with 2-aminoacridone (AMAC) are described. A total of 12 commercially available Hep/HS-derived unsaturated disaccharides were separated and unambiguously identified on the basis of their retention times and mass spectra. The constituent disaccharides of various samples, including unfractionated Hep/HS, fast-moving and slow-moving Hep components, and several marketed products, were characterized. Furthermore, for the first time, the saturated trisulfated disaccharide belonging to the nonreducing end of Heps was detected as being approximately 2% in unfractionated samples and ~15-21% in LMW-Heps prepared by nitrous acid depolymerization. No desalting of the commercial products prior to enzymatic digestion or prepurification steps to eliminate any excess of AMAC reagent or interference from proteins, peptides, and other sample impurities before RP-HPLC-Fd-ESI-MS injection were necessary. This method has applicability for the rapid differentiation of pharmaceutical Heps and LMW-Heps prepared by means of different depolymerization processes and for compositional analysis of small amounts of samples derived from biological sources by using the highly sensitive fluorescence detector.

The aim of the present study was to investigate whether tinzaparin sodium (a low-molecular-weight heparin (LMWH)) was fully and permanently neutralized in vivo in man by protamine sulphate (PS) after intravenous (i.v.) or subcutaneous (s.c.) injection. Fifty healthy adults equally divided in five age- and sex-matched groups were included. The groups received 50 IU unfractionated heparin (UH)/kg body weight (b.w.) i.v., 50 anti-factor Xa (anti-Xa) IU tinzaparin/kg b.w. i.v., 75 anti-Xa IU tinzaparin/kg b.w. s.c., 175 anti-Xa IU tinzaparin/kg b.w. s.c., or 1 ml of saline s.c. PS was given as a 10 min infusion in a dose of 1 mg/100 IU of heparin in the four first groups while 0.5 mg PS/kg b.w. was given in the placebo group. In the i.v. groups PS was administered 45 min after the heparin injection, and in the s.c. groups 180 min post-heparin injection. In the UH group PS fully and permanently neutralized all three activities. In the i.v. tinzaparin group PS reversed 80% of the anti-Xa activity, while the anti-IIa and aPTT activities were fully reversed. A slight, but statistically significant, increase in anti-Xa and anti-IIa activities were seen following i.v. tinzaparin. In the s.c. groups 60-65% of the observed peak anti-Xa activity was neutralized, anti-IIa was almost completely reversed, and aPTT returned nearly to baseline values. A gradual return of the anti-Xa activity (65-75%), anti-IIa activity (55%) and aPTT activity (35-45%) was seen in the s.c. groups 3 h after reversal compared with the observed peak values.(ABSTRACT TRUNCATED AT 250 WORDS)

In addition to inhibition of platelet aggregation, GPIIb-IIIa antagonists may reduce thrombotic events via other mechanisms. In a novel whole blood flow cytometric system, we investigated the effects of GPIIb-IIIa antagonists, in the presence or absence of thrombin inhibitors, on platelet surface-bound factor V/Va and platelet surface phospholipids. Diluted venous blood was incubated with either buffer or a GPIIb-IIIa antagonist (abciximab, tirofiban, or eptifibatide). Some samples were pre-incubated with clinically relevant concentrations of unfractionated heparin (UFH), a low molecular weight heparin, a direct thrombin inhibitor, or buffer only. Platelets were then activated and labeled with mAb V237 (factor V/Va-specific) or annexin V (binds phosphatidylserine), fixed, and analyzed by flow cytometry. In the absence of thrombin inhibitors, GPIIb-IIIa antagonists (especially abciximab) significantly reduced agonist-induced platelet procoagulant activity, as determined by reduced binding of V237 and annexin V. At high pharmacologic concentrations, unfractionated heparin and enoxaparin, but not hirudin, further reduced factor V/Va binding to the surface of activated platelets in the presence of GPIIb-IIa antagonists. Agonist-induced platelet procoagulant activity was reduced in a patient with Glanzmann's thrombasthenia. We conclude that GPIIb-IIIa antagonists reduce platelet procoagulant activity in whole blood and heparin and enoxaparin augment this reduction. Fibrinogen binding to GPIIb-IIIa is important in the generation of platelet procoagulant activity.

Oil-induced mononuclear phagocytes (MN) were quantitatively assayed for various hydrolases as unfractionated suspensions of frozen and thawed cells. They apparently contain two proteases. The first, measured with urea- or acid-denatured hemoglobin, was similar to purified Proteinase I of lung with respect to pH optimum (pH 4), stability, hydrolytic and polymerizing activities, and reactions to various inhibitors. The second protease resembled chymotrypsin in its hydrolysis of glycyl-L-phenylalanine amide, acetyl-L-tyrosine ethyl ester and N-benzoyl-DL-phenylalanine-beta-naphthol ester (BPN). With the latter, its pH optimum was between 5.0 and 5.8, and its action was inhibited by diisopropylphosphorofluoridate (DFP) and p-chloromercuribenzoate. When assayed under the above conditions, polymorphonuclear exudate cells (PMN) and red blood corpuscles (RBC) manifested little or no hydrolysis of either hemoglobin or BPN. MN also contained esterases that split methyl butyrate and beta-naphthyl acetate. The pH optimum with the latter was 7.4, and its hydrolysis was partially inhibited by DFP, fluoride, taurocholate, and eserine. PMN had low esterase activity; RBC had little or none. MN, but not PMN or RBC, contained a stable lipase with a pH optimum of 6.1 in maleate buffer. Protamine, NaCl, heat, p-chloromercuribenzoate, ethylenediamine tetraacetate, taurocholate, and DFP were inhibitory, but no appreciable activation occurred in the presence of heparin or serum. Thus it possessed some of the characteristics of Korn's lipoprotein lipase, but not others.