Effect of oral nimodipine on platelet function.

BACKGROUND AND PURPOSE: Nimodipine, a calcium antagonist, has been reported to have beneficial effects in acute ischemic infarction. Some calcium channel antagonists have antiplatelet effects. We investigated the effect of oral nimodipine on platelet function in healthy volunteers. METHODS: Twelve healthy volunteers (6 men and 6 women, mean age 32.9 +/- 5.6 years) took 30 mg nimodipine every 6 hours for 24 hours, followed by a week with no medication, followed by 60 mg every 6 hours for 24 hours. Ex vivo platelet function was measured at baseline, 1 hour after the first dose at each dosage strength, and 1 hour after the last dose at each dosage. Platelet studies included aggregation and adenosine triphosphate release in response to collagen, epinephrine, and adenosine diphosphate; maximal rate of primary aggregation; threshold adenosine diphosphate concentration for second-phase aggregation; and thromboxane B2 release at threshold aggregation. The bleeding time was measured at baseline and after the last 60-mg dose of nimodipine. RESULTS: No change in any platelet function study was seen with 30 mg nimodipine every 6 hours. Platelet function studies were also unchanged after 60 mg every 6 hours, except for a slight decrease in aggregation and adenosine triphosphate release in response to suprathreshold (10 microM) adenosine diphosphate (p = 0.001, Student's paired t test). There was no significant change in bleeding times. CONCLUSIONS: Oral nimodipine has minimal antiplatelet activity in young, healthy subjects.

Time course of platelet activation following acute ischemic stroke.

To assess the time course of platelet activation after acute ischemic stroke we measured the platelet protein ß-thromboglobulin (BTG) in 66 patients. Serial samples were obtained over a 3-month period. Mean values of BTG in patients with lacunar infarction were not significantly elevated at any time. In nonlacunar strokes, the mean BTG level during the first week after stroke was not significantly elevated. The mean BTG level rose in the second week and became statistically different from control (mean ± SEM; 33.1 ± 3.6 vs. 21.3 ± 2.0 IU/ml, p = 0.01). Mean values then declined to normal. Significant differences were noted among stroke subtypes. During the first week, mean values of BTG were higher in cardioembolic stroke (36.9 ± 6.2 IU/ml, p = 0.007 vs. controls) than in atherothrombotic stroke (22.1 ± 2.8 IU/ml, p = 0.82). By the second week, mean BTG values were significantly elevated for both cardioembolic (44.4 ± 8.3 IU/ml, p < 0.001) and atherothrombotic (33.8 ± 5.0 IU/ml, p = 0.01) strokes. The rise of this marker following stroke suggests that at least some of the platelet activation associated with stroke is a secondary phenomenon. Cardioembolic stroke is associated with as much platelet activation as atherothrombotic stroke and may have greater platelet activation during the first week after stroke.

Platelet and fibrin metabolism in recipients of the Jarvik 7 total artificial heart.

Recipients of the total artificial heart are at risk for device-related thrombus formation and thromboembolism. Platelet and fibrin metabolism was studied in four patients who received the Jarvik 7 total artificial heart as a bridge to transplantation and in eight patients after orthotopic heart transplantation. Platelet activation was assessed by measurement of plasma levels of beta-thromboglobulin, fibrin formation by fibrinopeptide A, and fibrinolysis by cross-linked fibrin degradation products. These markers were increased after surgery with only minimal differences between the two patient groups for the first 3 days. In comparison to heart transplant patients, these markers remained elevated in artificial heart recipients despite anticoagulation therapy. beta-Thromboglobulin levels did not decrease in two artificial heart recipients who received aspirin. Markers of platelet and fibrin activity were greatly increased in one artificial heart recipient who had impaired inflow into the device, was not anticoagulated because of bleeding, and had extensive device-related thrombus on explantation. Plasma markers of platelet and fibrin metabolism provide biochemical assessment of in vivo thrombus activity in artificial heart recipients. Monitoring these markers may provide an additional means of guiding anticoagulation therapy in patients with artificial hearts and assessing interventions designed to reduce device-related thrombus formation.

Hemostatic markers in acute stroke.

To assess the time course of thrombosis and fibrinolysis after acute stroke, we measured concentrations of fibrinopeptide A (FpA), B-beta 1-42 peptide (B-beta 1-42), B-beta 15-42 peptide (B-beta 15-42), and crosslinked D-dimer (XDP) in 31 patients at varying times following acute ischemic stroke and in 13 neurologically stable patients with chronic strokes. FpA levels were markedly elevated during the first week after stroke and declined slowly during the first month. Mean FpA levels were not significantly elevated in chronic stroke patients. Mean XDP levels were slightly elevated during the first week and increased during the next 2 weeks after stroke. B-beta 1-42 and B-beta 15-42 levels were not elevated at any time following acute stroke. Our data suggest that fibrin formation greatly exceeds endogenous fibrinolysis during the acute phase of ischemic stroke. Endogenous fibrinolysis develops slowly following stroke. Prolonged elevation of FpA concentration suggests that thrombin activity and fibrin formation continue for up to 4 weeks in some patients with ischemic stroke.

Fibrin metabolism in patients with acute myocardial infarction during and after treatment with tissue-type plasminogen activator.

In order to define some of the determinants of successful thrombolysis and reocclusion during fibrinolytic therapy for acute myocardial infarction (AMI), specific molecular markers of fibrin metabolism were serially measured in 15 patients with AMI treated with tissue-type plasminogen activator (t-PA). Fibrin formation was assessed by measurement of fibrinopeptide A (FpA) and fibrinolysis by assay of B-beta peptides 1-42 and 15-42 and crosslinked fibrin degradation products (XDP). At baseline, FpA levels were high while markers of fibrinolysis were near normal. Following a 90-minute infusion of t-PA (0.5-1.1 mg kg-1 hr-1), all markers of fibrinolysis increased. Levels of FpA remained elevated despite heparin at the initiation of cardiac catheterization. None of these markers discriminated between patients with successful reperfusion from those without. At 4 hours, B-beta 15-42 peptide and XDP levels remained elevated suggesting persistence of fibrinolysis beyond the short circulatory half-life of t-PA. FpA levels at 4 hours were lower in patients who underwent acute coronary angioplasty compared to those who received additional low dose t-PA (12.3 +/- 4.5 vs. 30.4 +/- 5.5 ng/ml, p less than 0.05). By 48 hours, markers of fibrinolysis had returned toward normal except in 2 patients with persistently elevated B-beta 15-42 peptide levels who suffered reocclusion on days 5 and 6 (75 and 44 vs. 29 +/- 3 nM, p less than 0.005). In conclusion, molecular markers of fibrin metabolism during fibrinolytic therapy may provide clinically relevant data.

Acute cigarette smoke exposure causes lung injury in rabbits treated with ibuprofen.

We studied lung clearance of aerosolized technetium-labeled diethylenetriamine pentaacetic acid (99mTcDTPA), plasma concentrations of 6-keto-PGF1 alpha and thromboxane B2, and pulmonary edema as indices of lung injury in rabbits exposed to cigarette smoke (CSE). Forty-six rabbits were randomly assigned to 4 groups: control sham smoke exposure (SS, N = 9), sham smoke exposure ibuprofen-pretreated (SS-I, N = 10), CSE (N = 9), sham smoke exposure ibuprofen-pretreated (SS-I, N = 10), CSE (N = 9), and CSE ibuprofen-pretreated (CSE-I, N = 19). Ibuprofen (cyclooxygenase eicosanoid inhibitor) was administered as a single daily intramuscular injection (25 mg/kg) for 7 days before the experiment. Cigarette or sham smoke was delivered by syringe in a series of 5, 10, 20, and 30 tidal volume breaths with a 15-min counting period between each subset of breaths to determine 99mTcDTPA biological half-life (T1/2). In the ibuprofen pretreated group, CSE caused significant decreases in 99mTcDTPA T1/2 and dynamic lung compliance. Furthermore, these changes in lung function were accompanied by severe injury to type I alveolar cell epithelium, pulmonary edema, and frequently death of the rabbits. These findings suggest that inhibition of the cyclooxygenase pathway before CSE exacerbates lung injury in rabbits.