Hemostatic function, survival, and membrane glycoprotein changes in young versus old rabbit platelets.

Although in vitro studies have demonstrated functional differences between young and old platelets, in vivo differences have not been precisely established. Therefore the in vivo hemostatic function of young and old platelets and the survival time have been examined in rabbits. The hemostatic function was measured by performing serial ear bleeding times in irradiation-induced thrombocytopenic rabbits. After irradiation with 930 rad the platelet count gradually diminished reaching a nadir ( approximately 20 x 10(3)/mul) at 10 d. The platelets present in the circulation, 7-10 d after irradiation, were considered old platelets, and the platelets present after recovery, 11-14 d postirradiation, young platelets. The measurement of platelet size was consistent with the hypothesis that platelets become smaller with age: the mean size was 3.84 mum(3) for old platelets and 5.86 mum(3) for young platelets. Regression analysis of the relationship between the bleeding time and the platelet count in 18 rabbits showed a significantly different slope for rabbits with predominantly old platelets compared with rabbits with predominantly young platelets (P < 0.001). Young platelets were more effective giving much shorter bleeding times than old platelets at comparable platelet counts. Survival times of young and old platelets were measured using platelets harvested on day 8 postirradiation (old platelets) and day 12 postirradiation (young platelets) that were labeled and then reinjected into normal recipient animals. The mean platelet survival time, calculated by gamma function, of old platelets was 28.8 h; of young platelets, 87.4 h; and of normally circulating heterogeneous platelets, (normal platelets) 53.0 h. Notably, the survival of old platelets was found to be exponential, and of young platelets, linear. Analysis of the membrane glycoproteins in young, old and normal platelets indicated that there was no qualitative difference amongst the young, normal, and old platelets. The relative relationship among all the glycoprotein peaks was equal and the only changes observed were quantitative, with young platelets having significantly more membrane glycoprotein per cell than old platelets and normal platelets. Normal platelets had intermediate concentrations of each glycoprotein. These results demonstrate that young platelets are hemostatically more effective in vivo than old platelets. The data are compatible with the hypothesis that platelets age in the circulation by losing membrane fragments and then after becoming senescent, are removed from the circulation by a random process.

Niacin-induced clotting factor synthesis deficiency with coagulopathy.

Although coagulopathy is a well-known complication of severe niacin-induced hepatotoxic reaction, it is not found in patients with minimal aminotransferase level elevations. Three patients with significant clotting factor synthesis deficiency and coagulopathy (prothrombin times, greater than 1.5 times control) from sustained-release niacin had only mild aminotransferase level elevations (1.5 to 2.0 times normal). In each case, protein deficiency, coagulopathy, and aminotransferase level elevation resolved promptly after withdrawal of niacin therapy. In one case, this syndrome recurred after rechallenge with sustained-release niacin, whereas the coagulopathy did not recur in a second patient rechallenged with crystalline niacin. Deficiency in protein synthesis, including coagulation factors, and coagulopathy are unrecognized complications of sustained-release niacin therapy. These cases indicate the need to measure prothrombin times routinely in patients who develop even mild aminotransferase level elevation while receiving sustained-release niacin therapy. These data are important in light of the increasing use of sustained-release niacin in the treatment of patients with lipid disorders.

Clinical and physiologic studies of two siblings with prekallikrein (Fletcher factor) deficiency.

Two siblings with hereditary Fletcher factor (prekallikrein) deficiency were studied for alterations of fibrinolysis, platelet function, skin inflammatory responses, permeability factor (PF/dil) formation and leukocyte chemotaxis. In vivo stimulation of fibrinolytic activity was normal; the bleeding time and platelet functions (adhesivity, aggregation, release reaction) were also normal. Both immediate (wheal-flare reaction to histamine, bradykinin, prostaglandin E1, physical agents) and delayed sensitivity skin test reactions were within normal limits. Migration of subjects' leukocytes to attractants in skin windows and in Boyden-type chambers was the same as that of control leukocytes. Serum complement components were essentially normal. One subject's leukocytes showed normal tissue factor production on stimulation by endotoxin, although prekallikrein deficiency did impair the endotoxin-stimulated generation of serum procoagulant activity. PF/dil caused increased vessel permeability in human skin; in vitro generation of PF/dil required both the Hageman factor and prekallikrein. The Fletcher factor-deficient subjects responded in a normal manner to PF/dil. Based on the Fletcher factor-coagulation assay, the biologic half-disappearance time of prekallikrein (after the transfusion of normal plasma in one of the subjects) was estimated at 35 hours. Therefore, these studies suggest that severe prekallikrein (Fletcher factor) deficiency in man is not associated with any clinically significant impairment in hemostasis, fibrinolysis, inflammatory responses or leukocyte function.

Factors predisposing to supraventricular tachyarrhythmias after coronary artery bypass grafting.

Supraventricular tachyarrhythmia (SVT) is a common complication of coronary artery bypass grafting. Four hundred twenty-four cases of coronary artery bypass grafting were retrospectively reviewed and 64 patients (15%) were identified who had clinically significant SVT. Sixty randomly selected arrhythmia-free patients served as controls. The arrhythmia group differed from the control group in age (62 +/- 8 years vs 57 +/- 8 years p less than 0.0001), radiographic cardiomegaly (19 of 64 patients with arrhythmia vs 6 of 60 control subjects, p less than 0.01), and echocardiographic left atrial enlargement (16 of 38 vs 6 of 37 control subjects, p less than 0.025). No significant differences existed regarding sex of the patient, prior myocardial infarction, reduced ejection fraction, history of congestive heart failure, occurrence of perioperative myocardial infarction or pericarditis, or pump time. The relative risk of SVT developing in patients 60 years or older was 1.91; in patients 60 years or older with cardiomegaly, 2.39; in patients 60 years or older with left atrial enlargement, 3.29; and in patients 60 years or older with cardiomegaly and left atrial enlargement, 3.47. Thus, it may be possible to select patients at relatively higher risk of having SVT who could especially benefit from preventive measures.

Effect of suloctidil on platelet function in patients with shortened platelet survival time.

The effect of suloctidil (600 mg/day) on platelet survival time (PST) and plasma and urine betathromboglobulin (BTG) was studied in a double-blind, placebo-controlled six-week crossover trial in 13 patients with shortened PST (less than 110 hrs, exponential model). Mean PST after suloctidil (110.6 hrs) was significantly higher than in the placebo phase (94.5 hrs) (p = 0.04). Mean plasma BTG was significantly lower during the suloctidil phase (42.8 ng/ml) compared with the placebo phase (65.8 ng/ml) (p = 0.02), but there was no significant difference in urine BTG. These results suggest that suloctidil provides a platelet protective effect and therefore may be of benefit in reducing the frequency of platelet mediated thromboembolic events.

Platelet survival determination in atherosclerosis.

Platelet survival presently represents a useful method for the study of atherosclerosis and its consequences in patients and in animal models. The currently used technique, while time consuming, appears to be reliable and reproducible for the measurement of platelet survival and turnover rate. The test offers promise to detect and perhaps quantify the degree of active vessel wall damage. In addition, it might prove useful to identify drugs with potential as platelet suppressants. Finally, the test might be used to compare with new techniques developed or used to identify vessel damage or thrombosis proneness.

Cardiac thromboembolism: evidence for role of platelets and value of platelet suppressant therapy.

Thromboembolism remains a frequent and serious problem in cardiac patients. Methods to identify the thrombosis prone patient and the identification of safe and effective forms of treatment would be of great value. The accumulating evidence which indicates that abnormalities in platelet tests are often present in cardiac patients and may help identify those at greatest risk of thrombosis is encouraging. It suggests that patients with cardiac disease are desirable groups for investigation. It also indicates that the platelet survival test may be useful as a reference against which new and more practical tests can be compared, as well as a means to identify useful platelet suppressant drugs or to monitor the effects of these drugs.

Anticoagulation in cardiac diseases. Prevention and control of thromboembolic events.

Thrombosis is a common feature of cardiac diseases. In valvular heart disease, anticoagulant therapy is recommended to prevent an initial embolic episode in high-risk patients or recurrent episodes in patients who have had an embolic event. Prophylaxis is recommended for patients over age 40. For patients with prosthetic heart valves, chronic anticoagulant therapy is recommended immediately after surgery, followed by long-term use of oral anticoagulants. Moderate doses of subcutaneous or intravenous heparin should be given for at least two weeks in patients with acute transmural infarction, unstable angina, or sudden cardiac arrest. In addition, anticoagulation is currently recommended for use in patients with chronic cardiomyopathy associated with congestive heart failure or atrial fibrillation.

Management of venous thromboembolism.

Venous thromboembolism is a frequent cause of morbidity and mortality, especially in immobilized elderly patients. Once thrombosis exists, heparin is effective to arrest the process, and occasionally thrombolytic therapy with urokinase or streptokinase is indicated to accelerate lysis. Thrombosis may be prevented by one or a variety of prophylactic measures which should be applied in high-risk patients.