Jeanne M. Corrao

Intravenous nitroglycerin-induced heparin resistance :a qualitative antithrombin III abnormality

An ability of intravenous nitroglycerin to interfere with the anticoagulant properties of intravenous heparin would have profound clinical implications. To investigation nitroglycerin-heparin interactions, the following pilot study was performed. Patients (N = 18) admitted to the coronary care unit with a diagnosis of either acute myocardial infarction or unstable angina were divided into four treatment groups: (1) intravenous nitroglycerin and intravenous heparin; (2) intravenous nitroglycerin alone; (3) intravenous heparin alone; or (4) neither intravenous nitroglycerin nor intravenous heparin. Serial determinations of activated partial thromboplastin time (APTT), serum heparin concentration, antithrombin III (ATIII) antigen (ATA), and ATIII activity (ATC) were obtained over a 72-hour period. Overall, patients receiving intravenous nitroglycerin did not differ significantly from other patients in APTT, heparin dose, heparin concentration, ATA, ATC, or ATA/ATC ratio (ATR). However, patients receiving intravenous nitroglycerin at a rate exceeding 350 micrograms per minute had a lower APTT (p less than 0.05), lower ATC (p = 0.02), higher ATR (p = 0.004), and a larger heparin dose requirement than patients receiving lower infusion rates. ATR correlated directly (r = 0.91; p less than 0.05) and ATC inversely (r = -0.78; p less than 0.05) with the intravenous nitroglycerin dose. Serum heparin concentration did not correlate with the intravenous nitroglycerin dose. Intravenous nitroglycerin-induced heparin resistance occurs at a critical nitroglycerin dose. A nitroglycerin-induced qualitative ATIII abnormality may be the underlying mechanism.

Rupture of the interventricular septum complicating acute myocardial infarction: A multicenter analysis of clinical findings and outcome

Acute ventricular septal rupture in the setting of acute myocardial infarction continues to present clinicians with a difficult therapeutic dilemma. The role of surgical intervention and its timing remains unresolved. A collaborative study from three institutions was undertaken to examine various clinical outcomes in 46 patients with ventricular septal rupture. No medically treated patient survived hospitalization. Since only surgically treated patients survived, we focused our evaluation on those characteristics that might differentiate surgical survivors from surgical nonsurvivors. Systolic blood pressure, pulse, mean right atrial pressure, left ventricular systolic pressure, and cardiopulmonary bypass time were univariate predictors of hospital survival. Multivariate analysis revealed that systolic blood pressure, right atrial pressure, and cardiopulmonary bypass time were strongly predictive of survival (p less than 0.05). In addition, taken together systolic blood pressure and right atrial pressure identified a group of persons who wee much more likely to survive surgical intervention. The results of this study may prove useful in predicting the risk of surgical repair in patients with ventricular septal rupture.

Bedside coagulation monitoring in heparin-treated patients with active thromboembolic disease: A coronary care unit experience

Patients with active venous and arterial thromboembolic disorders are known to benefit from systemic anticoagulation with heparin. Clinical studies have shown, however, that therapeutic anticoagulation is rarely achieved rapidly and often is not maintained over time. Prolonged laboratory turnaround time of the activated partial thromboplastin time (aPTT) may contribute directly to these common problems. A total of 272 aPTT determinations were performed on 120 heparin-treated patients admitted to the coronary care unit. The time from sample collection to data availability was 126 +/- 84 minutes with standard laboratory aPTT testing. In contrast, a bedside coagulation device provided an aPTT within 3 minutes (p < 0.001). Subtherapeutic aPTT values (< 65 seconds) were documented in 21% of all patients; in each, the heparin dose was changed and a repeat aPTT was required. In a separate study of 33 heparinized patients randomized to either bedside or central laboratory aPTT testing (264 aPTT determinations), the time to achieve a therapeutic state of systemic anticoagulation was 8.2 hours and 18.1 hours, respectively (p < 0.005). The time from aPTT determination to a decision regarding heparin titration adjustments was 14.5 minutes and 3 hours with bedside and laboratory testing, respectively (p < 0.001). Thus bedside coagulation monitoring provides a convenient, rapid, and accurate assessment of systemic anticoagulation among heparin-treated patients with active thromboembolic disease in the coronary care unit. This technology warrants further clinical investigation.

Impact of thrombolytic therapy on left ventricular mural thrombi in acute myocardial infarction

Abstract Left ventricular (LV) mural thrombi have long been recognized as a complication of acute myocardial infarction (AMI). Recent echocardiographic studies suggest an incidence of 2 to 18% in patients with AMI. Anterior infarctions are found to have a much higher incidence of mural thrombus than inferior infarctions. 1 Previous reports have noted conflicting results regarding the effect of thrombolysis on the formation of LV mural thrombi after AMI. 2–4 The aim of this study was 2-fold: to examine if systemic thrombolytic therapy using either tissue plasminogen activator or streptokinase reduces the incidence of LV mural thrombi early after AM1 compared with conventional treatment, and to determine if reperfusion of the infarct-related artery was associated with a lower incidence of LV mural thrombi.

Coronary Heart Disease Risk Factors in Women

Although men and women share a number of coronary risk factors including age, hypertension, cigarette smoking, diabetes, obesity, plasma lipoprotein concentration, and family history, the overall impact of these factors on the incidence and clinical manifestations of coronary heart disease (CHD) may differ. Additional risk factors which solely impact upon women include the use of oral contraceptives, menopause, and postmenopausal hormones. The impact of psychosocial and behavioral factors on CHD risk in women requires further investigation given that our current knowledge of traditional risk factors alone inadequately predicts all cases of CHD.

Hemorrhagic potential of combined diltiazem and recombinant tissue-type plasminogen activator administration

In the Thrombolysis in Myocardial Infarction (TIMI) phase II study, use of calcium channel antagonists at study entry was associated with an increased risk of intracerebral hemorrhage. Whether the observed association was due solely to chance, underlying cerebrovascular disease, or an effect of calcium channel antagonists themselves was not determined. Accordingly, blood loss from standardized ear incisions was measured in six groups of anesthetized New Zealand white rabbits: (1) saline control, (2) intravenous diltiazem (20 micrograms/kg/min x 60 minutes), (3) intravenous recombinant tissue-type plasminogen activator (rTPA) (1.0 mg/kg over 60 minutes, 10% bolus), (4) diltiazem plus rTPA, (5) diltiazem daily for 3 consecutive days, and (6) diltiazem (3 days) plus rTPA given on day 3. The combination of rTPA plus diltiazem (3 days) resulted in significantly more blood loss than rTPA alone, diltiazem (60-minute infusion), or rTPA plus diltiazem (60-minute infusion) (p = 0.003). Similarly, diltiazem (3 days) resulted in more blood loss than either agent alone or rTPA plus diltiazem (60-minute infusion) (p < 0.05). Thus, in this animal model, prolonged exposure to diltiazem with or without rTPA was associated with increased bleeding. The potential for chronic use of oral calcium channel antagonist to increase hemorrhagic risk after rTPA administration requires further investigation.

Platelet activation determined by flow cytometry persists despite antithrombotic therapy in patients with unstable angina and non-Q-wave myocardial infarction

Background: Current strategies in the treatment of patients with acute coronary syndromes include antiplatelet agents and thrombin antagonists, most commonly aspirin and heparin, respectively. Cardiac events, however, occur despite what is considered to be maximal medical treatment.Methods: We determined the percentage of activated platelets in whole blood samples taken from 22 patients with unstable angina and non-Q-wave myocardial infarction participating in the TIMI III B trial. Platelet activation was assessed using a monoclonal antibody to the surface-expressed α-granule protein, P-selectin, and flow cytometry. All patients received a full complement of antiischemic medications as well as intravenous heparin and oral aspirin, and were then randomized to tissue plasminogen activator or placebo.Results: Platelet activation prior to randomization was increased threefold to fourfold compared with healthy volunteers (11.4 ± 11.4% vs. 2.5 ± 2.0%; p < 0.01). Serial measurements performed 12, 24, 48, and 96 hours after treatment initiation revealed that platelet activation persisted. No differences in patients experiencing recurrent ischemic events (n=9) or those randomized to a 90-minute, accelerated infusion of tissue plasminogen activator (n=12) were observed.Conclusions: A modest degree of platelet activation is seen for at least 96 hours and possibly longer in patients with unstable angina and non-Q-wave myocardial infarction, despite being treated with intravenous heparin and oral aspirin. These findings support current efforts to identify more potent and selective antithrombotic treatment strategies.

Primary prevention of coronary heart disease in women

Despite the fact that coronary heart (CHD) disease is the leading cause of death among postmenopausal women, research on primary prevention of CHD in women has been relatively sparse. Prevalence of CHD risk factors such as cigarette smoking and hypertension remain high among US women. Moreover, common factors unique to women including pregnancy, oophorectomy, menopause, and use of steroid hormones, appear to have an impact on CHD risk that is often poorly understood. While postmenopausal hormone therapy is increasingly recommended for the prevention of CHD, the potential impact of nonpharmacologic measures such as changes in diet, exercise, and cigarette smoking have been relatively unexplored.

Dynamic nature of thrombin generation, fibrin formation, and platelet activation in unstable angina and non-Q-wave myocardial infarction

BackgroundThrombin and platelets are directly involved in arterial thrombosis, typically occurring at sites of atherosclerotic plaque rupture among patients with acute coronary syndromes. Understanding the dynamic nature of pathologic thrombosis has important clinical implications.MethodsFibrinopeptide A (FPA), thrombin-antithrombin complexes (TAT), and prothrombin activation fragment 1.2 (F1.2), plasma markers of fibrin formation (thrombin activity) and thrombin generation, and platelet activation, determined by the recognition of a surface-expressed platelet α-granule protein, P-selectin, using flow cytometry, were measured in 36 consecutive patients with unstable angina and non-Q-wave myocardial infarction participating in the Thrombolysis In Myocardial Ischemia (TIMI) III B trial.ResultsThrombin generation (TAT 12.1 ± 17.8 ng/ml vs. 3.4 ± 1.0 ng/ml; F1.2 0.19 ± 0.14 nmol/1 vs. 0.12 ± 0.8 nmol/1), fibrin formation (FPA 15.8 ± 23.5 ng/ml vs. 7.5 ± 2.3 ng/ ml), and platelet activation) 10.6 ± 2.4% vs. 2.5 ± 2.0%) were increased significantly in patients compared with healthy, age-matched controls (p < 0.01). Fibrin formation, represented by plasma FPA levels, did not correlate with the percentage of activated platelets (r=− .10, p=0.69). Thrombin generation and platelet activation also did not correlate. A statistically insignificant trend between TAT and platelet activation was observed (r=.42, p=0.07); however, even with TAT levels in excess of 20 ng/ml (nearly sixfold greater than normal healthy controls) platelet activation was increased by only 1.7-fold.ConclusionsThrombin generation, fibrin formation, and platelet activation are increased modestly among patients with unstable angina and non-Q-wave myocardial infarction. Despite the involvement of platelets and coagulation proteins in arterial thrombotic processes, their relative contributions may vary, providing a pathophysiologic basis for the dynamic expression of disease and response to treatment observed commonly in clinical practice.

Surface 12-Lead Electrocardiographic Findings and Plasma Markers of Thrombin Activity and Generation in Patients with Myocardial Ischemia at Rest.

Background: Myocardial ischemia at rest is typically associated with atherosclerotic coronary artery disease, atheromatous plaque rupture, and intracoronary thrombosis. In areas of advanced disease and vascular injury, the extent of thrombus is influenced largely by a delicate balance of procoagulant factors, favoring thrombus initiation, growth, and development, and anticoagulant factors, attempting to limit potentially flow-limiting coronary thrombosis. Thrombin, a 308 amino acid serine protease, is considered the most potent procoagulant factor in the setting of acute vessel wall injury, playing an essential role in the conversion of fibrinogen to fibrin, accelerating the prothrombinase complex, activating platelets, and stabilizing fibrin polymers. The purpose of this study was to determine the relationship between electrocardiographic abnormalities and markers of thrombin activity and generation among patients with unstable angina and non-Q-wave myocardial infarction.Methods and Results: In a study of 36 patients (59.1 ± 11.0 years) with myocardial ischemia at rest participating in the Thrombolysis in Myocardial Ischemia (TIMI) IIIB trial, thrombin activity in plasma, as determined by fibrinopeptide A (FPA), prothrombin fragment 1.2 (F 1.2), and thrombin-antithrombin III complexes (TAT) concentrations, were found to be increased significantly when compared with healthy volunteers (p < 0.004). Thrombin generation was also increased modestly compared with age-matched patients with stable coronary artery disease undergoing elective cardiac catheterization. Given that the surface 12-lead electrocardiogram (ECG) is frequently abnormal in patients with ischemic chest pain at rest and represents a readily available, first-line diagnostic test for assessing disease activity and treatment response, we investigated whether ECG abnormalities and thrombin activity/ generation in plasma were correlated. Twenty-six patients (72%) had ECG changes compatible with myocardial ischemia at the time of study entry, including 18 (50%) with newly inverted T waves (or pseudonormalization), 14 (39%) with reversible ST-segment depression, and 4 (11%) with transient (<30 minutes) ST-segment elevation. Within the predefined ECG groups there were no differences in plasma thrombin activity between patients with and those without confirmed abnormalities. Similarly, there were no differences in either plasma thrombin activity or generation between the predefined ECG groups.Conclusion: Although ECG abnormalities supporting the presence of myocardial ischemia occur commonly in patients with chest pain at rest, they do not correlate closely with markers of thrombin activity and generation in plasma. The diagnostic and prognostic capabilities of these diagnostic tools, considered either alone or together, require further investigation.