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.

Modification of thrombogenic factors in cardiac disease.

Thrombosis plays an important role in the development and course of most disorders affecting the heart. No effective methods are available to eliminate the thrombogenic stimulus for those conditions requiring the use of antithrombotic agents for prophylaxis or to arrest a thrombotic event. Available platelet and coagulation inhibitors are effective when properly selected and administered.

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.

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.

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 tests and antiplatelet drugs in coronary artery disease.

This study was designed to clarify discrepancies in the literature concerning platelet survival time and beta-thromboglobulin (beta TG) levels in patients with coronary artery disease (CAD) and the effect of platelet-suppressant drugs on these tests. Platelet survival time and plasma beta TG levels were determined in 48 patients with angiographically documented CAD. The effect of sulfinpyrazone or aspirin/dipyridamole on these measurements was investigated in a double-blind, crossover trial that included a placebo phase. In patients with CAD, the mean plasma beta TG concentration was significantly elevated, but the mean platelet survival time was not significantly different from that in controls. Treatment with sulfinpyrazone or aspirin/dipyridamole did not produce changes in platelet survival time or plasma beta TG concentration that were significantly different from the values during the placebo phase. This study demonstrates that compared with the spontaneous variation in platelet survival time or beta TG concentration, there was no measureable effect of sulfinpyrazone or aspirin/dipyridamole on the results of the tests.

Platelet release and thromboxane synthesis in symptomatic coronary artery disease.

The incidence and significance of platelet activation in myocardial ischemia was evaluated by serial measurement of plasma thromboxane B2 (TXB2) and beta thromboglobulin (beta TG) in plasma and urine in 98 patients admitted to a coronary care unit with chest pain. All measurements were normal in the 26 patients with noncardiac chest pain. Mean plasma TXB2 and beta TG concentration, but not urine beta TG, were elevated in the 25 patients with myocardial infarction and the 47 patients with angina. The beta TG levels remained normal in 61% of the patients with angina or infarction. The TXB2 levels were significantly higher in patients with recurrent episodes of angina at rest than in those without ischemic episodes after admission. There was a weak correlation between plasma TXB2 and plasma beta TG (r = 0.20, p less than 0.01) and between plasma and urine beta TG (r = 0.31, p less than 0.01). Results indicate that platelets are frequently activated with myocardial ischemia or infarction. However, the measurement of beta TG and TXB2 is of limited value in detecting or differentiating myocardial ischemia from infarction and therefore lacks clinical value in the management of patients with ischemic heart disease.

Platelet consumption in cardiovascular disease.

Many tests have been devised to investigate the role of platelets in arterial or venous thromboembolism. The mechanisms of platelet reactivity that the tests have measured have been variable and the early studies have been of little value in determining the contribution of platelet consumption in thromboembolic diseases. More recently, tests of in vivo platelet release and of platelet survival and turnover have been introduced and thought to be of great potential in the investigation of thromboembolic disorders. However, the data published thus far using more tests are far from conclusive that platelet activation and consumption occurs in thromboembolic disorders associated with arteriosclerosis. It may be that they are neither sensitive nor specific enough to detect minor changes in platelet activation. There is, however, some consistency that in conditions involving the larger vessels, prosthetic surfaces, or in association with active and recurrent venous thromboembolism, platelet release and platelet consumption measured by platelet survival time may occur. In particular, the abnormal results are consistently found in acute and recurrent venous thromboembolism, cardiac valve replacement with the older prosthetic devices, and arteriosclerosis of the larger arteries with clinical episodes of thromboembolism. However, in coronary artery disease, cerebrovascular disease, and peripheral vascular disease, the data are inconclusive, probably because the tests lack sensitivity. In addition, the value of the tests in the management of patients with thromboembolic disorders appears to be limited.

Plasma betathromboglobulin and serum fragment E in acute partial stroke.

Plasma betathromboglobulin (BTG) and serum fragment E (FgE) were measured serially by radioimmunoassay for 7 d in 67 patients admitted with acute partial stroke. Twelve patients progressed within 7 d of admission. Plasma BTG was not different from normal in patients with acute partial stroke and did not increase significantly with stroke progression. Serum FgE was elevated in patients with acute partial stroke compared with normal values, and was significantly higher in patients who progressed compared with those who remained stable. The results indicate that fibrin formation may be more important in the process of stroke progression than activation of platelets.

Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis.

Previously, we compared fixed low doses of heparin with adjusted doses of warfarin for the long-term treatment of venous thrombosis; in that study low-dose heparin was ineffective in preventing recurrence in patients with proximal-vein thrombosis. We have now completed a randomized trial comparing adjusted doses of heparin and of warfarin for prevention of recurrent venous thromboembolism in patients with proximal-vein thrombosis. One hundred six consecutive patients with acute proximal-vein thrombosis confirmed by venography were treated with intravenous heparin and then randomized to secondary prophylaxis. Two of 53 patients receiving heparin, as compared with one of 53 receiving warfarin, had new episodes of objectively documented venous thromboembolism. Nine patients taking warfarin had bleeding complications (which were major in three patients), as compared with one patient taking heparin (P = 0.008). Our data indicate that adjusted-dose subcutaneous heparin therapy provides an effective alternative to warfarin sodium and is associated with a lower risk of bleeding.

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.

Plasma and urine beta-thromboglobulin concentration in patients with deep vein thrombosis.

Plasma and urine beta-thromboglobulin (BTG) were measured in 52 patients with established deep vein thrombosis (DVT) and in 100 patients with clinically suspected DVT but with a negative venogram. Both plasma BTG (geometric mean 54: 95% range 12--239 ng/ml) and urine BTG (0.25; 0.03--3.1 ng/ml) were significantly elevated (p less than 0.005) in patients with DVT compared to symptomatic patients with a negative venogram (plasma BTG 32, 9--112 ng/ml; urine BTG 0.12, 0.02--0.58 ng/ml). Sensitivity (35%) and specificity (80%) of the plasma BTG assay for the diagnosis of DVT were low. The urine BTG assay had a sensitivity of 37% but a specificity of 100%. There was a significant correlation between plasma and urine BTG (r = 0.68, p less than 0.005). Serial BTG measurements were made in urine (40 patients) and plasma (20 patients) from high-risk neurosurgical cases who were screened with 125I-fibrinogen leg scanning and impedance plethysmography. BTG was elevated postoperatively and returned to normal within 2 or 3 days, but rose again in 10 patients in association with the development of DVT. The rise of BTG preceded the uptake of 125I-fibrinogen and lasted for only a few days. The return to normal of BTG was not related to treatment with anticoagulants. While measurement of BTG in plasma and urine is of limited value in the clinical diagnosis of venous thrombosis, the data indicate platelet activation occurs in venous thrombosis, but is maximal or perhaps limited to the initial phase of thrombus development.