Elevation of plasma fibrinogen in silent myocardial ischaemia.

High plasma levels of fibrinogen and plasminogen activator inhibitor (PAI-1) are reported to be correlated with coronary heart disease. Therefore the level of fibrinogen concentration in plasma was examined and verified for the possible correlation with the previously explored PAI-1 antigen and PAI-1 activity in the pathogenesis of premature atherosclerosis (Grzywacz et al., 1998, Blood Coagul Fibrinol. 9, 245-249). Examination included only men, aged 33-46 years, who were in a stable condition for at least six months after the acute event. They were divided into two subgroups: group A (n = 14) with and group B (n = 15) without ischaemic changes in 24 h Holter electrocardiogram. The number of involved vessels visible on the coronarography picture was similar in both groups. In the patients of group A the mean level of fibrinogen (3.92 vs 3.23 g/l, P < 0.05) was higher than in the controls (n = 15). No statistically differences were found between group B and control healthy subjects in any of the parameters measured. There were no correlation between fibrinogen concentration and PAI-1 antigen and activity levels, which were elevated in both groups of patients according to our previous study. Our results indicate that elevated levels of plasma fibrinogen and PAI-1 appeared in the group of patients with more severe disease, as revealed by silent myocardial ischaemia.

Impairment of plasma fibrinolysis in young survivors of myocardial infarction with silent ischaemia.

The aim of this study was to compare fibrinolytic parameters in two subgroups of young survivors of myocardial infarction: group A (n = 14) with silent myocardial ischaemia and group B (n = 15) without silent myocardial ischaemia, as assessed by 24 h Holter electrocardiogram monitoring. Only men aged 33-46 years who were in a stable condition at least 6 months after the acute event were included in the survey. All patients were normolipaemic or had only mild hyperlipidaemia, non-diabetic, normotensive, non-current smokers and with a normal body mass index. The control group consisted of 15 age-matched healthy men. Blood samples were taken at 7.30 a.m. In the group A patients, we found higher mean levels of tissue plasminogen activator (t-PA) total antigen (11.1 versus 6.9 ng/ml, P < 0.01), its inhibitor plasminogen activator inhibitor-1 (PAI-1) antigen (58.1 versus 34.8 ng/ml, P < 0.01), PAI-1 activity (4.9 versus 3.4 U/ml, P < 0.05) and tPA-PAI-1 complexes (5.1 versus 3.5 ng/ml, P < 0.05) as well as a lower level of t-PA activity (0.5 versus 0.8 IU/ml, P < 0.01) and free t-PA antigen (0.8 versus 1.3 ng/ml, P < 0.01) compared with the controls. However, group A patients exhibited higher PAI-1 antigen levels (58.1 versus 41.6 ng/ml, P < 0.05) than those without silent ischaemia. There were no differences between group B and controls in any of the parameters measured. Our results indicate that patients with more severe disease, as revealed by silent myocardial ischaemia, had lower levels of free t-PA as a result of the excess of PAI-1.

[Changes in tissue plasminogen activator in experimental peritonitis caused by pathogenic factors]. / Zmiany aktywnosci tkankowego aktywatora plazminogenu w doswiadczalnym zapaleniu otrzewnej wywolywanym róznymi czynnikami patogennymi.

Significantly higher tissue plasminogen activator activities were found in the abdominal exudate of rats with peritonitis caused by Escherichia coli than in rats with peritonitis caused by Staphylococcus aureus and Candida albicans. The changes of intraabdominal fibrinolysis may be depended on the type of microorganism.

Low molecular weight heparin and the heparin mobilisable pool of platelet factor 4 are reduced in young survivors of myocardial infarction.

The platelet factor 4 (PF4) mobilisation properties of low molecular weight heparin (Fraxiparine, Sanofi Winthrop, France) in young survivors of myocardial infarction (YSMI) and healthy volunteers have been investigated. The study group consisted of 42 YSMI less than 44 years old, all of them with angiographically proven occlusive coronary artery disease, studied 6 to 24 months after the acute event. The control group was composed of 30 healthy men of similar age. Subjects from the study and control groups were allocated to the following subgroups: those receiving 60 or 120 IU/kg b.w. of standard heparin (Polfa Kutno, Poland) and those receiving 60, 120 or 180 IC anti-Xa U/kg b.w. of low molecular weight heparin (Fraxiparine, Sanofi Winthrop, France) as a single intravenous injection. Additionally, in five YSMI patients the influence of prolonged aspirin administration (0.3g daily for more than 30 days) on the Fraxiparine mobilsable pool of PF4 and beta-thromboglobulin (beta-TG) concentration in the plasma was determined after injection of 180 IC anti-Xa U/kg b.w. of the drug. The PF 4 and beta-TG concentration in the plasma was evaluated using enzyme immunoassay methods before heparin or Fraxiparine intravenous injection and 2, 5, 10, 20, 30 and 60 min after. In both, the control and YSMI groups baseline PF4 levels were found to be normal. Moreover, similar marked dose-dependent increases of PF4 concentration in the plasma measured after 60 and 120 IU/kg b.w. of heparin as well as after 60 and 120 IC anti-Xa U/kg b.w. of Fraxiparine was found. The administration of 120 IU/kg b.w. of heparin resulted in a reduced rise in plasma PF 4 in YSMI as compared to healthy controls. The same phenomenon was observed when 180 IC anti-Xa U/kg b. w. of Fraxiparine was injected intravenously. In YSMI treatment with aspirin had no influence on the Fraxiparine mobilisable pool of PF 4 or the beta-TG concentration in the plasma. These results suggest that mobilisable pool of platelet factor 4 in young survivors of myocardial infarction derives from the "nonplatelet pool" and that reduction of heparin- or Fraxiparine-releasable pool of PF4 may reflect an impaired endothelium function, probably due to atherosclerosis.

[Haemostatic defects in venous thromboembolic disease]. / Zaburzenia hemostazy w zylnej chorobie zakrzepowo-zatorowej.

The aim of this study was to assess the frequency of haemostatic defects in 78 patients with the history of venous thromboembolic disease. In all patients antithrombin III activity and in 50 of them protein C, in 53-protein S, in 49 activated protein C (APC) resistance, plasminogen, alfa-2-antiplasmin were measured. We found 35 patients with haemostatic defect: 3 patients with decreased protein C activity and one case with decrease of protein C both activity and antigen level; 15 patients with decreaced antithrombin III activity; 7 patients with decreased free protein S antigen level; 5 patients with APC resistance. In 4 patients we found more than one defect; 2 patients had decreased concentration of free protein S and APC resistance, one patient had decreased activity of both antithrombin III and protein C, one patient had decreased antithrombin III activity and free protein S antigen level. Plasminogen and alfa-2-antiplasmin levels were within the normal range. Family studies indicated hereditary thrombophilia in 6 families. Screening for thrombophilia is very important for the optimal prophylaxis and treatment of venous thromboembolic disease.

On the action of a heparan-like glycosaminoglycan (Hemovasal) on the mechanism of haemostasis and fibrinolysis.

Hemovasal produced by Manetti-Roberts, Florence, Italy, is a glycosaminoglycan obtained from porcine intestinal mucosa which belongs to the family of heparan sulfates. The substance was examined On 36 male survivors of myocardial infarction with an interval of at least 6 months after the acute event. No anticoagulants were given and ASA was withdrawn at least 2 weeks before the trial. Hemovasal was administered in 3 different i.m. doses as single injections. A further group received a daily oral dose of 300 mg for one week. A comparable placebo group of patients as well as a group of healthy volunteers was run in parallel. The coagulation profile showed only a slight prolongation of the aPTT, a trace of diminution of Antithrombin III and no activation of Heparin cofactor II. The fibrinolytic system showed an enhancement of the diurnal increase of t-PA without an alteration of the total increase of this activity. There was a considerable and highly significant diminution of the PAI-1 activity. This was dose dependent and could be found after i.m. as well as after oral administration. It was assumed that the thrombolytic effect which was repeatedly described was a consequence of the diminution of PAI-1.

[Function of platelets in patients with occlusive atherosclerotic arterial disease of the lower extremities]. / Czynnosc krwinek plytkowych u chorych na miazdzycowe niedokrwienie konczyn dolnych.

The platelet function as well as parameters of lipid metabolism and glucose tolerance were investigated in 30 men with occlusive atherosclerotic arterial disease of the low extremities (IIIB or IV Fontaine's stage). The platelet aggregation, platelet survival, activity of intraplatelet metabolism of arachidonic acid, radiofibrinogen binding to platelet, circulating platelet aggregates and both the activity of factor VIII and the concentration of von Willebrand factor antigen in the plasma were measured. In the majority of patients the impairment of platelet aggregation with ADP, enhancement of radiofibrinogen binding to platelets and an increase of factor VIII level in the plasma were established. There was an interrelationship between platelet dysfunction and disturbances of lipid metabolism. Platelet survival was shortened in patients with moderate hyperlipidemia and correlated with a concentration of HDL-cholesterol in the serum. The radiofibrinogen binding to platelets was the most pronounced in patients with severe hyperlipidemia and correlated with a concentration of total cholesterol in the serum. The results may suggest the potential usefulness of antiplatelet drugs in patients with occlusive atherosclerotic arterial disease.

The effect of a long-acting recombinant hirudin (PEG-hirudin) on experimental disseminated intravascular coagulation (DIC) in rabbits.

Reproducible disseminated intravascular coagulation in rabbits was provoked by two intravenous injections 24 hours apart of endotoxin from Salmonella enteritidis. There were mild symptoms of DIC before the second injection which considerably increased thereafter. In detail there was a sharp drop of the platelet count and a considerable diminution of Antithrombin III, of Protein C, Plasminogen and Antiplasmin as well as an appearance of fibrin monomer complexes and an increase of the aPTT. When PEG-hirudin in a single dose of 1 mg/kg BW was given simultaneously with the second injection of endotoxin the following alterations were observed: The drop of the platelet count and of the activities of Antithrombin III, Protein C, Plasminogen and Antiplasmin was significantly less pronounced. The fibrin monomer complexes were lower and the aPTT was less prolonged. The thrombin time, however, as a sign of a direct action of hirudin on thrombin was considerably more prolonged than in the controls. The combined effect of these alterations strongly points in the direction of a favourable influence of PEG-hirudin on the course of DIC. It is of special interest that 6 h after the intravenous injection of PEG-hirudin its full effect on the thrombin time was still detectable. This is apparently due to a longer half-life in circulation of PEG-hirudin than of natural hirudin.

[Evaluation of thrombotic risk in young men after myocardial infarction during a period of clinical stability]. / Ocena zagrozenia zakrzepowego u mlodych mezczyzn po zawale serca w okresie klinicznej stabilnosci.

The study was aimed at an evaluation of individualized indications for antithrombotic therapy for secondary prevention in a group of 40 young survivors (aged 30-40 years) of myocardial infarction, presenting a stable phase of coronary disease. The control group consisted of 19 healthy men, of approximately similar age distribution. The determinations concerned the following: in vitro ADP and collagen induced platelet aggregation, plasma fibrinogen concentration, factor VII, VIII and antithrombin III activity, protein C concentration, spontaneous fibrinolytic activity and fibrinolytic activity after venostasis, plasminogen and alpha-2 antiplasmin activity. Moreover, to determine correlations with hemostatic parameters lipids, apolipoproteins, glucose, uric acid plasma concentration as well as percentages of lipoproteins and glycolyzed hemoglobin were also studied. In the study group various hemostasis disturbances were found: an increased platelet aggregation induced by low concentrations of ADP, increased plasma fibrinogen concentration and factor VII activity, decreased protein C concentration and impaired plasma fibrinolytic activity after venostasis. Some correlations between hemostatic and lipids parameters were also observed. Results of the study have suggested necessity for the individualized antithrombotic prevention in young survivors of myocardial infarction with antiplatelet and/or anticoagulant drugs.

[Platelet activation in young men after myocardial infarction: its relation to metabolic coronary risk factors]. / Aktywacja plytek krwi u mlodych mezczyzn po przebytym zawale serca. Zaleznosc od metabolicznych czynników zagrozenia wiencowego.

Selected parameters of platelet function as well as their relationship with metabolic coronary risk factors are studied in a group of 40 young survivors (aged 30-40 years) of myocardial infarction, now presenting stable coronary disease. Nineteen healthy men, of approximately similar age-span, constituted the control group. The following parameters were determined: platelet survival half-time (via non-isotope method), intraplatelet activity of cyclooxygenase and lipoxygenase pathway of arachidonic acid (by measurements of malondialdehyde concentration before and after incubation with acetylsalicylic acid acid) and 125-I-fibrinogen binding to platelets. Moreover, the plasmatic concentration of total cholesterol, HDL-cholesterol, triglycerides, phospholipids, Apo A and B, total beta lipoproteins, glucose, uric acid as well as percentages of beta, prebeta, alpha lipoproteins and glycosylated hemoglobin were also studied. Platelet survival half-time in patients was significantly shortened (3.64 +/- 1.37 days) when compared with the control group (4.97 +/- 1.7 days). A higher intraplatelet activity of lipoxygenase pathway (2.02 +/- 0.62 and 1.49 +/- 0.54 nmol MDA/10(9) platelets, respectively) was also found. However, activity of cyclooxygenase pathway of arachidonic acid and 125-I-fibrinogen binding to platelets remained unchanged. Shortened platelet survival half-time and the hyperactivity of intraplatelet lipoxygenase pathway correlated with a reduced plasmatic concentration of HDL-cholesterol (r = 0.323, p less than 0.05 and r = -0.451, p less than 0.05, respectively). The remaining parameters of platelet function were not statistically related to metabolic risk factors. The values of platelet function indicators in subgroups of patients divided according to family history of coronary heart disease, oral glucose load test result, and submaximal exercise test result did not differ significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

[Acquired platelet storage pool deficiency in rheumatoid arthritis]. / Nabyta choroba puli magazynowej plytek krwi w przebiegu reumatoidalnego zapalenia stawów.

A 64-year-old woman with a 15-years-history of rheumatoid arthritis developed generalized hemorrhagic diathesis. Routine coagulation tests revealed a slightly diminished platelet count only. Platelet aggregation in vitro induced by ADP, collagen, thrombin, arachidonic acid and ristocetin were reduced. The patient's plasma aggregating activity was significantly diminished which was due to a decrease of the intraplatelet nucleotide pool. The number of mepacrine labelled bodies as well as dense bodies in electron microscopy was below the normal values as well. Moreover, the intraplatelet concentration of cyclooxygenase--malonylodialdehyde (MDA) and lipoxygenase pathway products were lowered. Total platelet immunoglobulin G and M contents were significantly increased. The platelet survival time (in vitro aspirin method) was slightly shortened. Finally the diagnosis of delta-acquired platelet storage pool deficiency (delta-SPD) was established and possibilities of treatment were discussed.

[Evaluation of platelet malondialdehyde and 12-hydroperoxyeicosatetraenoic acid in type I and II diabetic patients with ketoacidosis and after clinical complications]. / Ocena wewnatrzplytkowego stezenia malonylodialdehydu i kwasu 12-hydroperoksyeikozatetraenowego u chorych na cukrzyce typu I i II w stanie kwasicy oraz po uzyskaniu wyrownania.

In 33 insulin-dependent, I and II type diabetic patients the authors evaluated the intraplatelet concentration of 12-hydroperoxyeicozatetraenoic acid (12-HPETE) and malonylodialdehyde (MDA) which are the products of lipoxygenase (LO) and cyclooxygenase (CO) metabolism of arachidonic acid (AA) in blood platelets. Moreover, in all patients, determinations of cholesterol total lipids, phospholipids, triacylglycerols were performed as well as serum lipoproteinogram. The studies were done in diabetic ketoacidosis and 2 weeks after compensation of diabetes was attained. Sixty healthy persons, with no changes in the coagulation system, constituted the control group. In patients with diabetic ketoacidosis a higher intraplatelet concentration of 12-HPETE (7.2 +/- 4.0 nmol/10(9) platelets) was found as compared with the values observed in the control group (4.7 +/- 2.1 nmol MDA/10(9) platelets); p less than 0.01. Intraplatelet MDA concentration did not, however, show a statistically significant difference. When compensation of diabetes was obtained the mean intraplatelet 12-HPETE concentration fell to values close the normal ones (5.5 +/- 3.4 nmol MDA/10(9) platelets). Nevertheless, the results of comparative determinations of mean values of both 12-HPETE and MDA concentrations in ketoacidosis as well as in compensated diabetes did not show statistically significant difference. High intraplatelet 12-HPETE concentration in diabetic ketoacidosis may be a cause of the formation or intensification of atherosclerotic changes, typical of this group of patients. The studies did not prove any correlation between the intraplatelet concentration of AA metabolism products and blood glucose concentration and lipid metabolism products. Neither was there any correlation between 12-HPETE and MDA concentration and the duration of clinically symptomatic diabetes.

[Assessment of hemostasis in patients with myocardial infarction complicated by deep venous thrombosis]. / Ocena ukladu hemostazy u chorych na zawal serca powiklany zakrzepica zyl glebokich konczyn dolnych.

The study was carried out of 53 patients with acute myocardial infarction receiving no anticoagulant treatment. Changes were traced in certain indices of the blood clotting system and fibrinolysis in plasma in the first 14 days of the disease, with particular attention given to patients in whom during the hospitalization signs of deep vein thrombosis in the lower extremities appeared or a positive result was obtained of the test with 125I-fibrinogen. In a group of 9 patients with deep vein thrombosis developing during the observation, on the first day of myocardial infarction shortening of the kaolin-cephalin clotting time and considerable rise of the level of fibrinogen-fibrin (FDP) degradation products were noted in serum, and on the 14th day raised fibrinogen level and reduced exogenous fibrinolytic activity of the plasma were noted. Increased level of fibrinogen and FDP and exogenous and endogenous plasma fibrinolytic activity observed on the 7th day of the disease were not related to the development of thrombotic complications. The thrombin clotting time, platelet count, factor X level, protein C concentration and antithrombin III activity in the plasma were not significantly changed during myocardial infarction. The obtained results suggest a limited usefulness of the basic tests of the clotting and fibrinolytic systems for early diagnosis of deep vein thrombosis in acute myocardial infarction.

Fluctuation of thrombin-antithrombin III complex in patients with acute myocardial infarction: influence of low-dose heparin administration.

The haemostatic parameters were studied within 14 days of acute myocardial infarction (AMI) in 103 patients randomly allocated into a group receiving low-dose heparin or into a group treated without anticoagulants. Patients with isotopic evidence of deep vein thrombosis were excluded from the analysis. An important formation of thrombin-antithrombin III complex (TAT) in the plasma was detected in the early stage of the disease. It was accompanied by an activation of plasma intrinsic fibrinolysis (IF), an elevation of fibrinogen and its degradation products (FDP) and a reduction of extrinsic plasma fibrinolytic activity (EF) together with normal levels of factor X, antithrombin III (AT III), protein C and alpha-2-antiplasmin. Sequentially studies periods of the disease revealed a diminution of TAT complex concentration in the plasma on the seventh day of AMI together with a rise of the both plasma fibrinolytic activities (IF, EF) as well as an elevation of fibrinogen and its degradation products, returning to the initial values on the 14 day of AMI. In the patients treated with heparin the augmentation of TAT complex in the plasma was prolonged until the fifth day of AMI. Moreover, heparin administration was connected with significantly higher levels of AT III and protein C along with a lower concentration of factor X and FDP on the seventh day of the disease. The fluctuation of fibrinolytic activities (IF, EF) in the plasma was heparin-independent. The present results indicate that low-dose heparin treatment modulates the plasmatic fluctuation of TAT complex as well as factor X, AT III and protein C levels in patients with acute myocardial infarction.

Dialyzable factors from uremic serum increase 125I-fibrinogen binding by normal blood platelets.

The influence of uremic serum on 125I-fibrinogen binding by normal blood platelets after induction with adenosine diphosphate was evaluated. The study was performed on 12 hemodialyzed uremic patients. The control group included 12 healthy subjects. It has been demonstrated that the uremic serum from the patients before hemodialysis significantly augmented fibrinogen binding by normal blood platelets (33.8 +/- 11.8%) in comparison with control subjects (14.4 +/- 8.9%). After hemodialysis, fibrinogen binding was comparable with the control group (14.9 +/- 10.1%). Uremic toxins removable during hemodialysis are probably responsible for the potentiation of 125I-fibrinogen binding by platelets.

Mepacrine-labeled platelet dense-body number in patients with chronic uremia.

Dense bodies are platelet organelles that store adenosine diphosphate. We have estimated the number of platelet dense bodies in patients with chronic uremia treated conservatively, by peritoneal dialysis and by hemodialysis. All groups of patients and control subjects were found to have similar mean numbers of platelet dense granules. Analysis of platelet distribution according to number of dense bodies has shown that patients undergoing hemodialysis have a decreased percent of platelets with a greater number of granules.

The binding of 125I-fibrinogen to blood platelets in patients with chronic uraemia.

The binding of 125I-fibrinogen to blood platelets was assessed in 41 patients with chronic uraemia. The study was performed in three groups of subjects: treated conservatively, with haemodialysis and with peritoneal dialysis. Platelets from uraemic patients were shown to be more susceptible to fibrinogen binding than platelets from healthy subjects.