Glycoprotein IIb/IIIa integrin blockade.
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Animals↗
Biomedical subjects
S D Berkowitz
Publications and source records attributed to S D Berkowitz.
Economic assessment of low-molecular-weight heparin (enoxaparin) versus unfractionated heparin in acute coronary syndrome patients: results from the ESSENCE randomized trial. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events [unstable angina or non-Q-wave myocardial infarction].
BACKGROUND: In the ESSENCE trial, subcutaneous low-molecular-weight heparin (enoxaparin) reduced the 30-day incidence of death, myocardial infarction, and recurrent angina relative to intravenous unfractionated heparin in 3171 patients with acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction). No increase in major bleeding was seen. METHODS AND RESULTS: Of the 936 ESSENCE patients randomized in the United States, 655 had hospital billing data collected. For the remainder, hospital costs were imputed with a multivariable linear regression model (R2=.86). Physician fees were estimated from the Medicare Fee Schedule. During the initial hospitalization, major resource use was reduced for enoxaparin patients, with the largest effect seen with coronary angioplasty (15% versus 20% for heparin, P=.04). At 30 days, these effects persisted, with the largest reductions seen in diagnostic catheterization (57% versus 63% for heparin, P=.04) and coronary angioplasty (18% versus 22%, P=.08). All resource use trends seen in the US cohort were also evident in the overall ESSENCE study population. In the United States, the mean cost of a course of enoxaparin therapy was $155, whereas that for heparin was $80. The total medical costs (hospital, physician, drug) for the initial hospitalization were $11 857 for enoxaparin and $12620 for heparin, a cost advantage for the enoxaparin arm of $763 (P=.18). At the end of 30 days, the cumulative cost savings associated with enoxaparin was $1172 (P=.04). In 200 bootstrap samples of the 30-day data, 94% of the samples showed a cost advantage for enoxaparin. CONCLUSIONS: In patients with acute coronary syndrome, low-molecular-weight heparin (enoxaparin) both improves important clinical outcomes and saves money relative to therapy with standard unfractionated heparin.
Acute Disease↗
Modifiable risk factors for vascular access site complications in the IMPACT II Trial of angioplasty with versus without eptifibatide. Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis.
OBJECTIVES: This study was designed to identify potential predictors of vascular access site (VAS) complications in the large-scale Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT) II trial, which studied angioplasty with versus without a new glycoprotein (GP) IIb/IIIa receptor inhibitor (eptifibatide). BACKGROUND: GP IIb/IIIa receptor inhibition during coronary interventions has been associated with excess VAS complications. If other predictors of VAS complications could be identified, they might be manipulated to reduce complications. METHODS: A total of 4,010 patients undergoing percutaneous transluminal coronary revascularization (PTCR) were randomized into one of three bolus/20- to 24-h infusion arms: placebo bolus/placebo infusion; 135-microg/kg body weight eptifibatide bolus/0.5-microg/kg per min eptifibatide infusion; or 135-microg/kg eptifibatide bolus/0.75-microg/kg per min eptifibatide infusion. Heparin during the procedure was weight adjusted and stopped 4 h before sheaths were removed. Logistic regression modeling was used to identify independent predictors of VAS complications. RESULTS: VAS complications were more common in patients treated with eptifibatide (9.9% vs. 5.9% placebo-treated patients, p < 0.001). Multivariate analysis identified eptifibatide therapy (p < 0.0001), advanced age (p = 0.0001), longer time to sheath removal (p = 0.0002), stent placement (with intense post-stent anticoagulation) (p = 0.0004), female gender (p = 0.0006), PTCR within 24 h of thrombolytic therapy (p = 0.002), larger heparin doses during PTCR (p = 0.009), major coronary dissection (p = 0.03) and placement of a venous sheath (p = 0.04) as independent predictors of VAS complications. CONCLUSIONS: VAS complications may be reduced by early sheath removal, by avoiding placement of venous sheaths and by limiting heparin dosing to avoid excessive activated clotting times. Early sheath removal during inhibition of platelet aggregation by eptifibatide is feasible.
Aged↗
Occurrence and clinical significance of thrombocytopenia in a population undergoing high-risk percutaneous coronary revascularization. Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) Study Group.
OBJECTIVES: This study sought to determine the frequency of thrombocytopenia and its relation with clinical outcomes in high risk patients undergoing percutaneous coronary revascularization who received either the platelet glycoprotein (GP) IIb/IIIa receptor antagonist abciximab (ReoPro, c7E3 Fab) or conventional therapy. BACKGROUND: The development of thrombocytopenia on exposure to GPIIb/IIIa antagonists threatens the utility and economic viability of this drug class for patients with vascular disease. METHODS: We analyzed data from the Evaluation of c7E3 for the Prevention of Ischemic Complications trial (EPIC), a 2,099-patient, randomized trial of placebo, abciximab bolus or abciximab bolus plus a 12-h infusion during high-risk coronary revascularization. RESULTS: Thrombocytopenia (nadir platelet count <100 x 10(9)/ liter) developed in 81 patients (3.9%) during their hospital stay, with 19 (0.9%) developing severe (<50 x 10(9)/liter) thrombocytopenia. Both thrombocytopenia and severe thrombocytopenia were more frequent in the bolus-plus-infusion arm (5.2% and 1.6%, respectively) than in the bolus-only and placebo arms combined (p = 0.020 and p = 0.025, respectively). Acute profound thrombocytopenia developed in two patients in the bolus-plus-infusion arm. Patients with thrombocytopenia experienced more unfavorable clinical outcomes than those who did not develop thrombocytopenia, regardless of treatment assignment, but those with thrombocytopenia who received abciximab had fewer worse outcomes at 30 days. Multivariable logistic modeling revealed a lower baseline platelet count, older age and lighter weight to be important predictors of thrombocytopenia. In a logistic regression model, bolus-plus-infusion treatment was a significant predictor of thrombocytopenia (p = 0.016) and remained so after adjustment for procedures and baseline risk factors (p = 0.0077). CONCLUSIONS: Thrombocytopenia was associated with adverse clinical outcomes and excessive bleeding, but patients receiving abciximab fared better than those receiving placebo.
Abciximab↗
Progress in point-of-care laboratory testing for assessing platelet function.
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Humans↗
Relation between inhibition of platelet aggregation and clinical outcomes.
Despite a clinical trials experience in excess of 30,000 randomized patients, there is no definitive answer or agreement as to the relation between the level of inhibition of platelet aggregation and clinical outcome. Work with abciximab in the setting of percutaneous intervention would suggest that a level of platelet inhibition in excess of 80% provides the most favorable clinical benefit. Whether this applies to the small molecule inhibitors such as eptifibatide, tirofiban, and lamifiban is unknown and will require testing of the hypothesis in large-scale clinical trials. In the acute coronary syndromes, only the peptide and nonpeptide inhibitors have been studied independent of a need for percutaneous intervention. The level of platelet inhibition required to achieve maximal clinical benefit is unknown and awaits data from the large-scale unstable angina and myocardial infarction trials. Issues of combining heparin with GP IIb/IIIa inhibition and the platelet-altering effects of thrombolysis must be considered when examining what might be the optimal level of platelet inhibition that provides maximal efficacy while maintaining safety. Long-term therapy with the oral platelet inhibitors poses a particular challenge in determining an optimal level of treatment that renders clinical effectiveness while preserving safety. Large, ongoing clinical trials with these agents should provide insight into this question. Finally, given the complexity of using such potent therapies in any individual patient, there is a need for improved monitoring of the platelet inhibitory effect. Standard platelet aggregometry has its problems and limitations, as described, and is not a test that has wide-scale applicability. Whole blood aggregometry and other methods of rapidly assessing platelet function at the point of care have promise in this arena. In a clinical trial, such technology might allow better delineation of the population's pharmacodynamic response to an agent because it could be more widely applied and therefore more patients would be studied. In clinical practice, patients could be dosed individually so that a range of platelet inhibition could be achieved that was believed to provide optimal benefit and safety.
Biomarkers↗
Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. The Global Utilization of Streptokinase and Tissue Plasminogen activator for Occluded coronary arteries (GUSTO) I Investigators.
BACKGROUND: Although the benefit of thrombolytic therapy in reducing mortality in acute myocardial infarction is well established, the types of bleeding and risk factors for bleeding are less well described in large trials. METHODS AND RESULTS: We analyzed the baseline characteristics, outcomes, and incidence of bleeding by location, severity, and treatment assignment among 41,021 patients in the GUSTO-I trial of thrombolysis for acute myocardial infarction. Of the 40,903 patients for whom there were complete data, 1.2% suffered severe bleeding and 11.4% experienced moderate hemorrhage at a variety of sites. The most common sources of bleeding were procedure related. The thrombolytic regimen was strongly related to the incidence of bleeding; comparatively more bleeding was seen with the therapies of streptokinase plus intravenous heparin and the streptokinase and tissue plasminogen activator plus intravenous heparin combination. In multivariate analysis, the four most powerful independent predictors of hemorrhage were older age, lighter body weight, female sex, and African ancestry; they remained the most important predictors of bleeding when multivariate analysis was performed on patients who did not undergo invasive procedures. The presence of serious hemorrhage was associated with other undesirable outcomes (recurrent events, left ventricular dysfunction, arrhythmia, or stroke). CONCLUSIONS: Important predictors of bleeding in this population are increased age, lighter weight, female sex, African ancestry, and experiencing invasive procedures. Other nonhemorrhagic adverse clinical outcomes were associated with moderate and severe bleeding, which was in turn associated with increased length of hospital stay and mortality at 30 days.
Age Factors↗
Acute profound thrombocytopenia after C7E3 Fab (abciximab) therapy.
BACKGROUND: Platelets play a crucial role in the ischemic complications of percutaneous coronary procedures. The recent availability of c7E3 Fab (abciximab; ReoPro), a chimeric monoclonal antibody Fab fragment directed against the platelet glycoprotein IIb/IIIa receptor, has reduced abrupt closure and other adverse clinical events and lessened the need for revascularization procedures. As experience accrues, rare cases of acute profound thrombocytopenia have been revealed. METHODS AND RESULTS: From November 1991 to July 1996, patients at Duke University Medical Center who underwent percutaneous coronary revascularization and received their first exposure to c7E3 Fab were evaluated for the development of acute profound thrombocytopenia, defined as a platelet count < 20 x 10(9)/L occurring within 24 hours of initial treatment. Four patients (0.5%) developed acute profound thrombocytopenia within 11 to 21 hours of receiving the c7E3 Fab bolus. Nadir platelet counts ranged from 1 to 16 x 10(9)/L and occurred within 11 to 26 hours. No patient developed a significant hemorrhagic complication, and each patient's platelet count responded to platelet transfusion. Platelet counts remained depressed for at least 3 days but returned to baseline within 2 weeks. CONCLUSIONS: Acute profound thrombocytopenia can occur after c7E3 Fab administration. Its development was not predictable, and it requires consideration in every patient treated. A platelet count 2 to 4 hours after the bolus would likely have detected these four cases. When indicated, platelet transfusion will raise the platelet count to safer levels without adverse effects. The differential diagnosis (including heparin-induced thrombocytopenia), a plan for management, and postulates as to the mechanism are discussed.
Abciximab↗
Coagulation complicating cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia receiving the heparinoid, danaparoid sodium.
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Aged↗
Hemodilution with other blood reinfusion techniques in total hip arthroplasty.
Acute normovolemic hemodilution has been reported to result in blood savings varying from 18% to 90%. Very few of these are randomized prospective studies. This study attempts to determine the blood transfusion savings if acute normovolemic hemodilution is used in combination with autologous predonated blood and cell saver. Thirty-three patients undergoing total hip arthroplasty were assigned randomly to one of two groups (control, n = 16; hemodilution, n = 17). Patients in both groups entered an autologous predonation program if cleared medically and were placed on Cell Saver intraoperatively and in the postanesthesia care unit. In addition, the hemodilution group underwent acute normovolemic hemodilution preoperatively. Only 41% of the patients in the hemodilution group required any autologous blood transfusion as compared with 75% of the control group. In addition, the hemodilution group required a mean lower quantity of autologous blood transfusion (41% of the estimated blood loss) as compared with the control group (71%). The net anesthesia time increased by an average of 11.4 minutes in the hemodilution group. Acute normovolemic hemodilution is a safe procedure even in an older patient population. Hemodilution resulted in fewer patients needing autologous predonated blood transfusions. The major benefit of hemodilution was seen when predonation was not possible.
Adolescent↗
Efficacy and safety of low molecular weight heparin (ardeparin sodium) compared to warfarin for the prevention of venous thromboembolism after total knee replacement surgery: a double-blind, dose-ranging study. Ardeparin Arthroplasty Study Group.
UNLABELLED: We performed a double-blind, randomized clinical trial to compare the efficacy and safety of three different subcutaneous (s.c.) low molecular weight heparin doses (ardeparin sodium 25, 35, or 50 anti-Xa U/kg twice daily [BID]) to adjusted-dose warfarin (international normalized ratio [INR] = 2.0 to 3.0), as venous thromboembolism prophylaxis after total knee replacement surgery. The primary endpoint was total venous thromboembolism prevalence, defined as deep vein thrombosis discovered at postoperative venography of the operated leg, or symptomatic, objectively-documented pulmonary embolism. Of 860 patients randomized, 680 (79%) had an evaluable venogram or pulmonary embolism. The total venous thromboembolism prevalence was significantly greater among patients prophylaxed with warfarin compared to ardeparin 50 BID (38% vs 27%, p = 0.019); the prevalence among ardeparin 25 BID (37%) and 35 BID (28%) patients was similar to warfarin and ardeparin 50 BID patients, respectively. Overt bleeding occurred in 22 (7.9%) ardeparin 50 BID patients compared to 12 (4.4%) warfarin patients (p = 0.08), and in seven ardeparin 25 and 35 BID patients each (5.2% and 5.0%, respectively). Compared to the warfarin group, blood loss was significantly greater in the ardeparin 50 and 25 BID groups, and not different in the ardeparin 35 BID group. CONCLUSIONS: Postoperative, unmonitored, fixed-dose ardeparin 50 anti-Xa U/kg s.c. BID is significantly more effective than adjusted-dose warfarin for this indication. Although overt bleeding among warfarin and ardeparin 50 BID patients did not differ significantly, ardeparin 50 BID patients had significantly greater blood loss. Ardeparin 35 anti-Xa U/kg s.c.BID may provide efficacy similar to ardeparin 50 anti-Xa U/kg s.c. BID but with reduced bleeding.
Adult↗
Treatment of established deep vein thrombosis: a review of the therapeutic armamentarium.
Although it has never been evaluated by an appropriately designed clinical trial, there is a strong impression that acute symptoms of deep vein thrombosis (DVT) and pulmonary embolism (PE) are improved by heparin treatment. The first experimental evidence showing that anticoagulants were effective in reducing mortality from PE came in landmark study by Barritt and Jordon in Lancet in 1960. In 1986, Hull et al demonstrated that failure to attain an adequate anticoagulant effect with heparin in patients with proximal vein thrombosis is associated with a high rate of recurrence. Current practice favors admission to the hospital of patients with venous thromboembolism to be treated with intravenous (IV) heparin for at least 4-5 days, overlapped with initiation of warfarin. Four randomized trials evaluating continuous intravenous (CIV) vs. subcutaneous (SQ) heparin administration in the treatment of DVT found no significant differences in the observed rates of clinically important events. Thus, SQ route heparin is as efficacious and would allow treatment at home. Low molecular weight heparins, when released by the FDA for this indication, will make this more feasible.
Anticoagulants↗
Degradation of von Willebrand factor in patients with acquired clinical conditions in which there is heightened proteolysis.
The behavior of plasma von Willebrand factor (vWF) in patients with acute leukemia (n = 5), decompensated cirrhosis (n = 10), and acute pancreatitis (n = 5) was investigated to evaluate whether the systemic proteolytic states associated with these diseases had affected the structure and function of the molecule. vWF antigen and, to a lesser degree, ristocetin cofactor activity in patient plasma were high. Multimeric analysis of plasma vWF revealed loss of high molecular weight multimers. The subunit composition and proteolytic pattern of vWF immunopurified from patient plasmas and reduced were studied by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis followed by transblotting and probing with monoclonal antibodies that distinguish cleavages caused by plasmin from those caused by other proteases. There was marked reduction of the relative concentration of the native vWF subunit of 225 Kd in all patient groups, indicating heightened cleavage of the protein. The concentrations of 189- and 140-Kd vWF fragments, normally present in plasma, were increased in cirrhosis and pancreatitis but not in leukemia. Novel fragments, ranging in size from less than 225 to approximately 120 Kd were present in leukemia and cirrhosis, including plasmin-generated fragments of 176 and 145 Kd. These data indicate that in clinical conditions in which there is heightened proteolysis vWF is degraded in vivo by plasmin and other proteases. Degraded vWF may be less effective than native vWF in supporting primary hemostasis, thereby being a cofactor in the multifactorial bleeding diathesis accompanying systemic proteolytic states.
Acute Disease↗
Proteolysis of von Willebrand factor after thrombolytic therapy in patients with acute myocardial infarction.
In 20 patients with acute myocardial infarction (AMI) treated with streptokinase (SK, n = 7), recombinant single-chain tissue plasminogen activator (rt-PA, n = 7) or urokinase (UK, n = 6), the behavior of plasma von Willebrand factor (vWF) was studied before and 1.5, 3, 24, 48, and 72 hours after beginning thrombolytic therapy. vWF antigen (vWF:Ag) was high in plasma, especially after SK. The ristocetin cofactor (RiCof) activity of vWF, high before therapy, tended to decrease soon after therapy. This pattern of vWF changes was paralleled by the early loss of higher molecular weight multimers. By immunoblotting of immunopurified and reduced vWF and monoclonal antibody epitope mapping, we found that vWF was degraded after thrombolysis, especially after SK, as indicated by the higher values of two plasmin-generated fragments of 176 and 145 Kd. There were more plasmin-generated fragments in the five patients who had bleeding complications than in the remaining 15 who did not. In conclusion, quantitative and qualitative changes of vWF compatible with proteolytic degradation of the protein occur during thrombolytic therapy. Such degradation, roughly proportional to the degree of the general lytic state induced by each agent, might be a cofactor of the bleeding complications occurring in treated patients.
Fibrinolysin↗
Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor.
Proteolytic cleavage of the von Willebrand factor subunit may be important for processing and/or function of the molecule and is altered in certain subtypes of von Willebrand disease. It results in the generation of two main fragments with apparent molecular masses of 140 kDa and 176 kDa from the 225-kDa subunit. We have now obtained chemical evidence to locate the protease-sensitive bond between residues Tyr-842 and Met-843, a site that appears to reflect the specificity of calcium-dependent neutral proteases (calpains). Antibodies were raised against four synthetic peptides that represented sequences immediately preceding or following or including the cleavage site. One antibody (against the fragment from Ala-837 through Asp-851) reacted only with the intact subunit, and its epitope included the cleavage site. All others reacted specifically with either the 140-kDa or the 176-kDa fragment, demonstrating their origin from a single cleavage. In samples of purified von Willebrand factor from four of five patients with type IIA von Willebrand disease, the anti-peptide antibodies showed markedly decreased reactivity with either the 140-kDa or the 176-kDa fragment, suggesting the existence of distinct molecular abnormalities clustered around the cleavage site. Thus, in the majority of type IIA patients, a common pathogenetic mechanism may lead to the disappearance of the larger multimers as a consequence of structural changes that may expose a sensitive bond to the action of specific proteases. These studies demonstrate the use of anti-peptide antibodies directed at a relevant structural domain for the immunochemical differentiation of normal and mutant molecules.
Amino Acid Sequence↗
Sialic acid prevents loss of large von Willebrand factor multimers by protecting against amino-terminal proteolytic cleavage.
Removal of sialic acid from the von Willebrand factor (vWF) subunit exposes additional cleavage sites in the amino-terminal region that are associated with loss of large multimers. The extent of large multimer loss was evaluated by examining the sites of subunit cleavage of native and carbohydrate-modified vWF after treatment with trypsin, chymotrypsin, or plasmin. In the presence of proteinase inhibitors, purified vWF was treated with neuraminidase alone to remove 90% to 95% of the sialic acid or with neuraminidase and beta-galactosidase to remove the sialic acid and 45% to 50% of the D-galactose, with little or no loss of large multimers observed. Digestion of native vWF with trypsin produced the greatest loss of large multimers, while chymotrypsin produced less and plasmin produced the least. Large multimer loss was more extensive with each enzyme after carbohydrate modification of vWF. The extent and approximate location of subunit cleavage was determined by immunoblotting and monoclonal antibody epitope mapping. Trypsin, chymotrypsin, and plasmin were shown to produce both amino- and carboxyl-terminal fragments. The number, location, and relative quantities of carboxyl-terminal fragments produced were unchanged after carbohydrate modification. However, digestion of the amino-terminal region was considerably more extensive after carbohydrate modification as judged by a marked decrease or absence of the larger fragments seen when native vWF was digested, and by the appearance of new smaller molecular mass species. Therefore, the greater loss of large multimers that occurs after carbohydrate modification is likely to be the result of cleavages in the amino-terminal region of the molecule. By protecting the vWF subunit against amino-terminal cleavage, sialic acid inhibits the loss of large multimers.
Antibodies, Monoclonal↗
Evidence that calpains and elastase do not produce the von Willebrand factor fragments present in normal plasma and IIA von Willebrand disease.
Recent evidence suggests that proteolysis plays an important role in some forms of inherited and acquired von Willebrand disease (vWD). Because calpains and one or more enzymes released from polymorphonuclear leukocytes are known to proteolyze von Willebrand factor (vWF) in vitro with resultant loss of large multimers similar to that seen in IIA vWD, they have been suggested as being responsible for the proteolysis in vivo. Using monoclonal epitope mapping, we have examined the proteolysis of the vWF subunit by porcine calcium-activated neutral proteases (calpains) and human leukocyte elastase to determine whether they produce the vWF proteolytic cleavage products seen in normal individuals and IIA vWD. Purified vWF was digested with porcine calpains I and II. We found no difference in the size, location, and quantity of the fragments produced by calpain I v calpain II. New fragments were detected of approximately 200, 170, 150, and 125 Kd. There was no evidence for generation of the native 140 and 176 Kd fragments. Some loss of the native fragments was seen, which suggests that they were further cleaved. Epitope mapping of the 170- and 150-Kd calpain-cleaved fragments revealed them to be from different parts of the molecule than the regions from which the native 176- and 140-Kd fragments derived. This was further supported by determination of the amino-terminal sequence of the calpain-cleaved 170- and 150-Kd fragments. Digestion of vWF with human leukocyte elastase produced new fragments at 210/205, 190, 170/165, 145/140, and 130/125 Kd. No generation of native fragments was detected. Monoclonal epitope mapping of the 145/140-Kd elastase-cleaved band proved that it derived from the carboxyl-terminal portion of the vWF molecule, whereas the native 140-Kd fragment is derived from the amino-terminal end. Neither calpains nor human leukocyte elastase produced the proteolyzed fragments present in normal and IIA vWD and, therefore, probably do not cause the loss of large multimers that is seen in that disorder.
Amino Acid Sequence↗
Epitope mapping of the von Willebrand factor subunit distinguishes fragments present in normal and type IIA von Willebrand disease from those generated by plasmin.
A small but consistent proportion of the von Willebrand factor (vWF) in normal plasma is composed of 189, 176, and 140 kD fragments cleaved from the 225 kD subunit. A monoclonal antibody map of vWF, based on the reactivity of individual antibodies with cyanogen bromide and tryptic fragments of known carboxy and/or amino termini, showed that in normal and IIA von Willebrand disease (vWD) plasmas the 140 kD fragment was derived from the amino-terminal region, whereas the 176 kD fragment was derived from the carboxy-terminal region of the subunit. In type IIA vWD, however, the fragments comprised a greater proportion of circulating vWF. In contrast, plasmin cleaved a 176 kD fragment from the amino terminus and a 145 kD fragment from the carboxy terminus of the subunit. Species similar to these plasmin-cleaved fragments were demonstrated in plasmas from four patients treated with fibrinolytic agents, but not in IIA vWD.
Antibodies, Monoclonal↗