fibrinopeptide-a and Cerebrovascular-Disorders

Topics: Acetylcysteine; Aged; Analysis of Variance; Antithrombin III; Cell Aggregation; Cerebrovascular Disorders; Cytidine Diphosphate Choline; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Female; Fibrinogen; Fibrinopeptide A; Glutathione; Humans; Infusions, Intravenous; Leukocytes; Male; Middle Aged; Nootropic Agents; Reperfusion Injury; Rutin; Thromboembolism

Cerebrovascular events (CVE) in patients with prosthetic heart valves (PHV) have remained a severe and frequent complication despite oral anticoagulation with or without aspirin. We studied the possible pathophysiological involvement of platelet-derived microparticles (PMP) as a contributing factor for the increased incidence of CVE in patients with PHV.. We compared in a retrospective, case-control study the clinical outcome after the implantation of the PHV with several different independent morphological and functional methods, including simultaneous transcranial Doppler monitoring of both middle cerebral arteries, PMP detection by flow cytometry with use of platelet-specific antibodies, coagulation markers, and determination of the procoagulant activity by Russell's viper venom time, a phospholipid-dependent coagulation assay.. Eight of 26 patients with PHV had 9 CVE during 136 person-years of observation. Transcranial Doppler monitoring revealed an increased frequency of microembolic signals recorded over a 30-minute period in patients with CVE (75+/-25; median, 55; range, 27 to 248) compared with those without CVE (23+/-12; median, 7; range, 0 to 153; P<0.05) or with control subjects (0; P<0.001). Flow cytometry analysis showed increased levels of PMP in patients with compared to those without CVE (4.1+/-0.6% versus 2.4+/-0.4% of all fluorescence-positive events gated; P<0.05). Increased procoagulant activity was documented by the shortened Russell's viper venom time expressed as an increased level of platelet equivalents per microliter of plasma in patients compared with control subjects (+24.7+/-14.9%; P<0.01). Subgroup analysis revealed that patients with CVE had a higher excess of platelet equivalents per microliter of plasma than patients without CVE in relation to the controls (+68.7+/-36.7%; P<0.05). Mildly elevated thrombin-antithrombin III complexes (2.9+/-0.7; median, 2.3; normal, <2.0 microg/L) suggested incompletely suppressed thrombin formation, and fibrin generation (fibrinopeptide A) was in the upper normal range (2.1+/-0.2; median, 1.8; normal, <2.0 ng/mL), despite adequate anticoagulation (INR=3.6+/-0.1).. Our data show increased microembolic signals, platelet microparticles, and procoagulant activity in symptomatic patients with PHV and provide a potential pathophysiological explanation of CVE.

Topics: Antithrombin III; beta-Thromboglobulin; Blood Coagulation; Blood Platelets; Case-Control Studies; Cerebral Arteries; Cerebrovascular Circulation; Cerebrovascular Disorders; Female; Fibrin; Fibrinolysis; Fibrinopeptide A; Flow Cytometry; Heart Valve Prosthesis; Humans; Intracranial Embolism and Thrombosis; Male; Middle Aged; Peptide Hydrolases; Prothrombin; Prothrombin Time; Retrospective Studies; Thrombin; Ultrasonography, Doppler, Transcranial

The purpose of this study was to clarify differences in coagulation and fibrinolytic activation between the various subtypes and phases of ischaemic stroke. Haemostatic activation markers were measured in 52 patients with cardioembolic stroke, 32 with atherothrombotic stroke and 54 with lacunar stroke and compared with 23 age-matched controls. Data were obtained in the acute (< or = 7 days after onset), subacute (8-28 days) and chronic (> or = 29 days) phases of stroke. In patients with cardioembolic stroke, D-dimer and alpha 2-antiplasmin-plasmin complex levels were higher during the acute and subacute phases, while thrombin-antithrombin III complex levels were higher during the acute phase than in patients with lacunar stroke and controls. In cardioembolic stroke, fibrinopeptide A was increased during the acute and subacute phases, thrombin-antithrombin III complexes were higher during the subacute phase and D-dimer levels were higher during the chronic phase. Protein C activity was lower during the acute phase than in atherothrombotic stroke, lacunar stroke and controls. Protein C antigen was lower during the acute phase than in lacunar stroke and controls and during the chronic phase than in lacunar stroke. In contrast, only D-dimer levels were higher in atherothrombotic stroke patients than controls during the acute and chronic phases and no significant alterations in these markers were observed in the patients with lacunar stroke. These findings suggest that measurement of molecular markers of coagulation and fibrinolysis may be useful for detecting intracardiac thrombin and plasmin generation in patients with cardioembolic stroke.

Topics: Aged; alpha-2-Antiplasmin; Antifibrinolytic Agents; Antithrombin III; Arteriosclerosis; Cerebral Infarction; Cerebrovascular Disorders; Female; Fibrin Fibrinogen Degradation Products; Fibrinolysin; Fibrinopeptide A; Hemostasis; Humans; Intracranial Embolism and Thrombosis; Male; Middle Aged; Peptide Hydrolases

Treatment with warfarin using a target International Normalized Ratio (INR) range of 1.7 to 2.5 is efficacious for many clinical indications, but the minimal intensity of anticoagulation required for antithrombotic protection has yet to be determined. To evaluate whether patients could be reliably monitored with a less intense regimen, we anticoagulated patients with warfarin for several months using a target INR range of 1.3 to 1.6 as determined by prothrombin time (PT) using a sensitive thromboplastin (Dade IS, International Sensitivity Index [ISI] = 1.3). Plasma measurements of F1+2, a marker of factor Xa action on prothrombin in vivo, were also obtained to determine the suppressive effect of warfarin on hemostatic system activity. Overall, 20 of 21 patients with a history of cerebrovascular events (mean age, 61 years) could be reliably regulated with warfarin in the target INR range. F1+2 levels were significantly suppressed from baseline in all patients, with a mean reduction of 49% (range, 28% to 78%). We found a significant relationship between the extent of suppression of prothrombin activation levels and the baseline measurements. A mean reduction of 65% was observed for those patients with baseline F1+2 greater than or equal to 1.5 nmol/L, but only 38% for baseline F1+2 less than or equal to 0.5 nmol/L. Overall, 68% of plasma samples obtained during stable anticoagulation were within the target INR range. PTs were also determined on all plasma samples with two thromboplastins of lower sensitivity (C+, ISI = 2.09; and automated simplastin, ISI = 2.10). Only 47% and 35% of PT determinations, respectively, were within the target range with these reagents. We conclude that prothrombin activation can be significantly suppressed in vivo with use of warfarin in an INR range of 1.3 to 1.6. This level of anticoagulation can be reliably achieved by monitoring PTs with a thromboplastin of high sensitivity.

Topics: Blood Coagulation; Cerebrovascular Disorders; Female; Fibrinopeptide A; Humans; Intracranial Embolism and Thrombosis; Ischemic Attack, Transient; Male; Middle Aged; Monitoring, Physiologic; Peptide Fragments; Prothrombin; Prothrombin Time; Radioimmunoassay; Thromboplastin; Warfarin

The well-known coagulation inhibitors antithrombin and protein C, and the more recently described inhibitors, heparin cofactor II and extrinsic pathway inhibitor, were measured in plasma during a 7-day observation period, from patients with pneumonia (n = 13), and in stroke patients with infarction (n = 9) and haemorrhage (n = 9). In patients with pneumonia, elevated fibrinopeptide A levels and subnormal antithrombin and protein C levels suggested some degree of consumption of the inhibitors. Later, an increase was observed for all the inhibitors, but was most conspicuous for heparin cofactor II which reached high normal values. C-reactive protein, initially markedly elevated, decreased rapidly. This finding suggests that heparin cofactor II might act as a delayed acute phase reactant. In stroke patients only small, not statistically significant, changes occurred during the observation period, except for heparin cofactor II which increased in patients with haemorrhagic stroke.

Topics: Acute-Phase Proteins; Adult; Aged; Anticoagulants; Antithrombins; C-Reactive Protein; Cerebral Hemorrhage; Cerebral Infarction; Cerebrovascular Disorders; Female; Fibrinopeptide A; Glycoproteins; Heparin Cofactor II; Humans; Male; Middle Aged; Pneumonia

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.

Topics: Acute Disease; Aged; Aged, 80 and over; Cerebrovascular Disorders; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinopeptide A; Fibrinopeptide B; Humans; Male; Middle Aged; Peptide Fragments; Time Factors

The plasma concentrations of protein C, an anticoagulant protein, and fibrinopeptide A were measured in 37 patients with acute hemispheric stroke and in age-matched controls with nonvascular neurologic diseases. In 11 stroke patients who died within 15 days after the onset (nonsurvivors) protein C antigen concentration on admission was lower than in the control group (p less than 0.005), with a mean value of 63% of the concentrations found in the 26 survivors (p less than 0.001). The difference in protein C concentrations was not associated with different prothrombin time ratios and serum albumin concentration in survivors and nonsurvivors of stroke and was independent of the size of the cerebral lesion. Increased fibrinopeptide A concentration on admission was found in all stroke patients (p less than 0.001), but it was higher in nonsurvivors than in survivors (p less than 0.01), suggesting that lower protein C concentrations in nonsurvivors might be due to increased thrombin-dependent protein C activation. In survivors, protein C concentration was slightly but significantly higher than in controls (p less than 0.05) and was unchanged 2 months after stroke, a time when fibrinopeptide A concentrations had returned to normal. These results show that protein C is involved in the hemostatic derangement caused by stroke and provide a rationale for clinical trials evaluating the therapeutic supplementation with protein C of patients with acute ischemic stroke.

Topics: Acute Disease; Aged; Cerebrovascular Disorders; Fibrin; Fibrinopeptide A; Humans; Middle Aged; Protein C

Fibrinopeptide A (FPA), released from the fibrinogen A alpha-chain by thrombin, can be resolved by high-performance liquid chromatography (HPLC) into three forms, the intact peptide (A), a modified peptide phosphorylated at the serine in position 3 (AP), and an N-terminally degraded form (AY). A new method has been developed, using HPLC, that allows direct measurement of the proportions of AP, A, and AY released by thrombin from fibrinogen in plasma samples of 200 ul or less. The method was used to examine variations in the proportions of AP and AY expressed as a % of total FPA in a number of patient and control groups. The mean percentages of AP and AY of plasma fibrinogen were found to be 21.7 and 14.2%, respectively, in normal laboratory controls. In older, apparently normal, individuals these figures were 27.0 and 15.5%, respectively. Cord plasma exhibited very high AP and slightly reduced AY levels (41.6 and 12.4%, respectively) compared with normal adults. Patients with liver failure had low AP levels and high AY levels (11.6 and 21.1%, respectively). Patients recovering from major surgery or acute thrombotic stroke showed an acute-phase rise in fibrinogen level that was accompanied by an increase in AP and variable reduction in AY. Incubation of heparinized whole blood for 8 days in vitro demonstrated a gradual decrease in the proportion of AP and increase in AY of plasma fibrinogen. These results provide some support for the idea that an increased "aging" of fibrinogen in the circulation may result in a decrease in the AP content of fibrinogen accompanied by a more variable increase in AY.

Topics: Aged; Aged, 80 and over; Cerebrovascular Disorders; Chromatography, High Pressure Liquid; Female; Fetal Blood; Fibrinogen; Fibrinopeptide A; Humans; Infant, Newborn; Kinetics; Liver Diseases; Macromolecular Substances; Pregnancy; Rectal Neoplasms; Reference Values; Thrombin

Plasma levels of beta-thromboglobulin (BTG) and fibrinopeptide A (FPA), markers of platelet alpha-granule release and thrombin generation respectively, were measured in 27 subjects with transient cerebral ischaemic attacks (TIA), 43 age-matched controls, and 32 young controls. BTG and FPA were both higher in elderly controls than in young controls. BTG was higher in TIA subjects than in age-matched controls and higher in the 12 TIA subjects who had further vascular events in the next year than in those who had no further events. FPA was not significantly associated with TIA or with further events. These results support a relationship between platelet activation and TIA and suggest that BTG levels indicate a group at higher risk of further vascular events.

Topics: Adult; Age Factors; Aged; Aspirin; Beta-Globulins; beta-Thromboglobulin; Blood Platelets; Cerebrovascular Disorders; Dipyridamole; Female; Fibrinopeptide A; Humans; Ischemic Attack, Transient; Male; Middle Aged; Prognosis; Risk; Time Factors

When the human blood coagulation and fibrinolytic systems are activated thrombin cleaves fibrinopeptide A (FPA) and plasmin cleaves b beta1 leads to 42 from fibrin(ogen). Elevated plasma concentrations of FPA and B beta 1 leads to 42 are evidence for enhanced thrombin and plasma activities in plasma. We have determined the plasma concentrations of FPA and B beta 1 leads to 42 in patients who have had thrombotic stroke. Patients who were studied immediately following stroke were found to have greatly elevated plasma FPA and B beta 1 leads to 42 levels, but these decreased to the concentrations found in an apparently healthy age-matched control group 1 month after the infarct. In contrast, the plasma concentrations of the platelet release product beta-thromboglobulin (beta TG) were slightly, but significantly, elevated immediately following the stroke and these did not alter with time after the infarct. It is concluded that following thrombotic stroke increased thrombin and plasmin activities are to be found in plasma. These increased protease activities are probably not directly associated with an increased in vivo platelet release reaction and may be useful in deciding which patients are at risk of reinfarction or stroke progression.

Topics: Aged; beta-Thromboglobulin; Blood Coagulation; Cerebrovascular Disorders; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Fibrinopeptide A; Humans; Middle Aged; Peptide Fragments; Time Factors