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Biomedical subjects

D A Tsakiris

Publications and source records attributed to D A Tsakiris.

52 records · Page 3Linked to original sources
PubMed1993

Clinical pharmacology of intravenously administered recombinant desulfatohirudin (CGP 39393) in healthy volunteers.

Clinical pharmacology of the intravenously administered recombinant desulfatohirudin CGP 39393 was investigated in 47 healthy volunteers in a multicenter study. Mean peak concentrations after bolus injections of 0.1, 0.3, 0.5, and 1.0 mg/kg were 154, 443, 764, and 1,691 nmol/L, respectively. Intravenous infusions of 0.1 mg/kg/h for 6 h and of 0.2 and 0.3 mg/kg/h for 6 h and 72 h resulted in mean steady-state levels of 78, 227, and 312 nmol/L. Elimination was multiexponential and dose independent. Concordant pharmacokinetic parameters were obtained from both i.v. bolus and infusion experiments (overall average total plasma clearance, 2.20 ml/min/kg; mean residence time, 2.12 h; volume at steady state, 0.27 L/kg). Thrombin inhibition by CGP 39393 was demonstrated ex vivo by the thrombin chromogenic assay (TCA), by activated partial thromboplastin time (APTT), thrombin time (TT), and prothrombin time (PT). Following a parabolic function APTT doubled and quadrupled at CGP 39393 concentrations of 100 and 1,000 nmol/L, respectively. Whereas TTs (bovine thrombin 3 or 6 IU/ml) were very sensitive to low CGP 39393 levels with unmeasurable clotting times at CGP 39393 concentrations greater than 30 and 60 nmol/L, PT was prolonged by a factor of only 1.3 above baseline at 300 nmol/L. APTT appears to be most suitable for monitoring the anticoagulant effect of CGP 39393 over a broad concentration range. The drug was well tolerated without clinically relevant bleeding episodes or other adverse events.

Adult↗
PubMed1992

Anticardiolipin antibodies and coronary heart disease.

Arterial or venous thrombotic events have been described as complications in patients with positive anticardiolipin antibodies (aCL), affecting various organs including the heart. In order to see whether aCL could be, among others, a predisposing factor for coronary artery occlusions and whether it could serve as a prognostic marker for coronary heart disease, 232 patients enrolled in the European Concerted Action on Thrombosis Angina Pectoris Study were studied. aCL and various other haemostatic parameters were determined at time of admittance in order to see whether a relationship existed between haemostasis at baseline and extent or prognosis of the cardiovascular disease. A follow-up at 12 and 24 months after angiography included information about relapsing coronary or other thrombotic events, treatment and outcome of the disease. aCL were not found to be a marker of either progressive cardiovascular disease or recurrent thrombotic events. No correlation was found, either in aCL positive or in aCL negative patients, between high levels of haemostasis activation markers, such as beta-thromboglobulin, platelet factor 4 or fibrinopeptide A and recurrent cardiovascular disease.

Aged↗
PubMed1992

Lupus anticoagulants/anticardiolipin antibodies in patients with normal tension glaucoma.

Ocular vascular occlusive disease resulting in severe retinopathy and/or post-thrombotic glaucoma has been extensively discussed in patients with lupus anticoagulant and/or anticardiolipin antibodies (LA/aCL). Inadequate circulation plays an important role in the pathogenesis of another ophthalmic entity--the normal tension glaucoma. We studied 22 patients with normal tension glaucoma (group I) and 23 with chronic open-angle glaucoma (group II) and compared them with a control group (n = 25, group III). LA, aCL, the aCL cofactor beta 2-Glycoprotein I, and other haemostatic parameters including factor VIII:C, von Willebrand factor, factors II, V, VII and plasminogen activator inhibitor were measured. Five out of 22 (22.7%) in group I, five out of 23 (21.7%) in group II and three out of 25 (12.0%) in group III had positive LA and/or aCL. These prevalences were not statistically significantly different. beta 2-Glycoprotein I was normal in all groups. No other parameters were significantly different between groups. These findings do not support the contribution of ocular microvascular occlusive disease, due to elevated aCL, in the pathogenesis of glaucomatous damage.

Aged↗
PubMed1992

[Internal medicine therapy of venous thromboembolism].

Treatment of venous thromboembolism aims at the reduction of mortality of massive pulmonary embolism, the arrest of further thrombotic processes and at avoiding late post-thrombotic sequelae. Anticoagulation with heparin and oral anticoagulants remains the treatment of choice. Heparin is administered intravenously or subcutaneously for four to five days. Oral anticoagulation follows thereafter for three to six months or even life-long. Low molecular weight heparin will probably be able to substitute for the unfractionated heparin in the initial treatment phase. Therapeutic fibrinolysis or surgical treatment are considered as alternative treatment modalities. Furthermore, new potent thrombin or platelet inhibitors appear as promising future antithrombotics.

Anticoagulants↗
PubMed1991

[Tendency to thrombosis following bone marrow transplantation?].

Various thrombosis related parameters of the hemostatic system were evaluated in 11 patients who had had bone marrow transplantation (BMT). At 0, 1, 3 and 6 months after BMT, antithrombin III, heparin cofactor II, protein S (PS), factor VIII:C, von Willebrand factor (vWF:Ag, vWF:RiCof), tissue plasminogen activator (tPA), plasminogen activator inhibitor, thrombin antithrombin III complexes (TAT), d-dimers (DD) and antiphospholipid antibodies (APA) were determined. A statistically significant rise in the levels of vWF was observed after BMT, with a similar trend for tPA. High TAT and/or DD were detected in 10/11 patients and positive APA only in 5/11. Of the other parameters only free PS was permanently low, with normal total PS and C4bBP. These findings suggest persistent thrombin generation peri- and post-BMT. The significantly high vWF and the low free PS could foster a procoagulant state.

Blood Coagulation Factors↗
PubMed1991

[Profibrinolytic activity of recombinant hirudin?].

Recombinant hirudin (rH, CGP 39393) is a potent thrombin inhibitor. In addition to its anticoagulant effect, we investigated its profibrinolytic activity in vitro and ex vivo. The fibrinolytic activity of the euglobulin fraction of 15 normal plasmas with or without urokinase was tested in a fibrin plate assay both before and after addition of rH. The same cycle was repeated in 8 plasmas with heparin instead of rH. For the ex vivo evaluation 12 healthy volunteers received 0.1-0.3 mg/kg/h rH for 6 h. Blood samples were drawn at 0 h, 6 h, 12 h and 24 h and various fibrinolytic parameters were assayed. In the presence of rH or heparin a slightly stronger fibrinolytic effect was observed, measured as fibrin plate lysis activity, both when rH was added to plasma in vitro and when it was administered intravenously. However, this may be explained by the specific anticoagulant action of rH and heparin in the dynamic equilibrium of fibrinolysis and clotting in the test system. Moreover, under rH treatment the observed changes in the various fibrinolytic parameters could not be differentiated from the normal circadian rhythm of these proteins. There was no convincing evidence to indicate enhancement of plasma fibrinolytic activity by recombinant hirudin.

Adult↗
PubMed1991

[Heparin-induced thrombocytopenia. Perspectives in a therapeutic dilemma].

Severe heparin-induced thrombocytopenia (HIT) is a complication of heparin treatment with a frequency of about 0.5% of the treated patients. It is attributed to an immune mechanism leading to the production of heparin-associated antibodies which bind to the platelets and cause their elimination through consumption, sometimes accompanied by thromboembolic episodes. Therapeutically HIT represents a dilemma since heparin administration must be stopped immediately, whereas anticoagulation is acutely indicated in order to avoid thrombotic complications. Two such cases with this dilemma are illustrated. The diagnosis of HIT was made using platelet aggregation studies and flow cytometry techniques for the detection of heparin-associated platelet antibodies. Therapeutically, low molecular weight heparins were administered with success. Besides the diagnostic problems other available therapeutic solutions are discussed.

Aged↗
PubMed1990

Lupus anticoagulant--antiphospholipid antibodies and thrombophilia. Relation to protein C--protein S--thrombomodulin.

In order to define the behavior of the lupus anticoagulant and/or antiphospholipid antibodies, we investigated the possible association with protein C, protein S and thrombomodulin. In 19 patients with established diagnosis of an autoimmune disease and coexisting lupus anticoagulant protein C (antigen and activity), protein S (total and free), anticardiolipin and antiphosphatidylserine antibodies were estimated. In one case the IgG globulin fraction containing the inhibitor was separated. The activation rate of pure protein C to its activated form using thrombin/thrombomodulin as activator was then measured in the presence or absence of lupus anticoagulant. No overall decrease of protein C or protein S was detected in patients' plasma. Nevertheless, the lupus anticoagulant had a specific effect on the protein C system, inhibiting the catalytic activity of thrombomodulin without causing a functional protein C deficiency. This specific effect upon thrombomodulin can be a main cause, but not necessarily the only one, for the thrombophilic tendency of patients with the lupus anticoagulant.

Antibodies↗
PubMed1989

[Thrombin-antithrombin III complexes as a measure of effective heparin treatment?].

To study the effect of heparin on thrombin formation in vivo, we measured thrombin-antithrombin III complexes (TAT) in 26 patients treated with heparin for acute coronary artery disease or deep vein thrombosis. There was a statistically significant correlation between activated partial thromboplastin time and heparin concentration, but none was found between these tests and TAT. Abnormal TAT values in 45% of the patients showed that therapeutic heparin concentration did not inhibit thrombin formation in vivo, or did so only partially.

Antithrombin III↗
PubMed1989

Impaired fibrinolysis as an essential contribution to thrombosis in patients with lupus anticoagulant.

Lupus anticoagulants (LA) are IgG or IgM antibodies against phospholipids which in vivo represent an important thrombophilic factor despite their in vitro anticoagulant activity. We investigated the fibrinolytic system of 20 patients with connective tissue disease and positive LA, compared to a control group of 24 age- and disease-matched patients without LA. There was no statistically significant difference of alpha 2-antiplasmin, plasminogen, fibrinogen, t-PA activity, D-dimers and heparin cofactor II, between the two groups. Although t-PA was uniformly low in both groups, plasminogen activator inhibitor activity (PAI) was significantly higher in LA cases (p less than 0.001). Increased PAI levels represent an inhibitory factor of the fibrinolytic defense mechanism, which together with other functional deviations may contribute to the thrombophilic tendency of LA patients.

Autoantibodies↗
PubMed1986

Long lasting sitting position and haemostasis.

Blood coagulation, fibrinolysis and platelet aggregability were assessed in 8 physicians aged 30-40 years, who had travelled non-stop by car from Salonica to Athens (510 km) and returned to Salonica after 48 h of rest and after administration of 1 g of aspirin. At the end of journey A, platelet aggregability was found to be increased (6 out of 8 persons), AT III was decreased by 30% (p less than 0.001), the F VIII:C / F VIIIR: Ag ratio was decreased (p less than 0.02) and ELT was prolonged. At the end of journey B the findings were the following: platelet aggregation was not affected, the decrease of AT III was not statistically significant and ELT was significantly shortened (p less than 0.005). A common finding of both journeys was the increase of platelet counts at the end (p less than 0.005). The correlation between long lasting sitting and the response of the haemostatic balance is suggested. The influence of aspirin is discussed.

Adult↗
PubMed1985

The ratio MDA/MDAa as a new index of platelet hyperactivity.

Since 1979, malonyldialdehyde (MDA) is considered a sensitive index of platelet hyperactivity. Stimulators of phospholipase A2 are used in the procedure of MDA production in order to obtain the final quantity (MDAa) which corresponds to the total amount of arachidonic acid present; without stimulation the production of MDA is minimal in non-activated platelets (MDA non-activated). Therefore, the more the MDA/MDAa ratio approaches unity, the more activated are the thrombocytes. We utilized for the first time this new index for the investigation of hyperactive platelets, and we studied 56 persons (17 patients with thrombophilic disease as group A, 17 normals as group B and 22 diabetics without ketoacidosis as group C). We proved that the new index (MDA/MDAa) can be used to detect persons with functionally hyperactive platelets because large differences are found between the mean values of normals and the values of patients with established thrombotic disease, at a high confidence limit (means +/- 3 SD covering 99% of the samples). Comparing the sensitivity of this new index with the other three methods used for the detection of hyperactive platelets [ratio of circulating platelet aggregates (CPA), aggregation with ADP, spontaneous aggregation] in groups B and C we found that only the ratio MDA/MDAa was able to reveal that (a) the two groups B and C are not identical (a statistical conclusion after comparison with the other methods) and (b) there were 5 diabetics in group C who had more hyperactive platelets than the others (these patients were not detected by any other method).

Adenosine Diphosphate↗
PubMed1985

Effect of ticlopidine on coagulation and platelet functions during hemodialysis with cuprophan membranes.

The study is a comparison of two successive HD sessions on each patient. 60 min prior to the first session a placebo was administered orally, while to the second session 500 mg ticlopidine. Arterial blood samples for leucocyte and platelet counts, C3 complement, blood gases, beta-thromboglobulin (beta-TG) and platelet factor 4 (PF-4) measurement were taken before and 15, 30, 60, 120, 240 min during each HD session. Platelet aggregation (ADP 1 microM/ml) was also carried out pre and post-dialysis. It is suggested that ticlopidine: 1) prevents HD-induced complement activation and related phenomena, 2) normalize the increased plasma levels of platelet markers 3) inhibits the ADP-induced platelet aggregation.

Adult↗
PubMedDate not supplied

[Management of patients with Type 2B von Willebrand's disease during delivery and puerperium].

Von Willebrand's disease (VWD) is the most common congenital haemorrhagic diathesis inherited as an autosomal dominant trait, with a prevalence estimated to be 1 - 2 %. In subtype 2B an abnormally structured von-Willebrand factor (VWF) leads to an increased binding of VWF molecules to normal platelets, which regularly results in thrombocytopenia in pregnancy. Only few systematic observations in patients with type 2B VWD in the perinatal period have been reported in the literature. Six spontaneous deliveries in two sisters with type 2B VWD are reported. The first patient did not show any bleeding complications in five vaginal deliveries without any factor replacement therapy. The second patient showed a massive haemorrhage on the third postpartum day after administration of factor VIII-VWF concentrate replacement therapy (Haemate(R) HS), only on the day of delivery. No neonatal complications were reported. The clinical management of pregnancy, delivery and puerperium in patients with type 2B VWD requires close collaboration of experienced obstetricians, haematologists, anaesthesiologists and paediatricians. During labour and delivery, but especially in puerperium, there is a significantly increased risk for haemorrhage. Vaginal delivery is generally safe, but the incidence of postpartum haemorrhage is 30 %. These bleedings may be extremely severe. The danger of postpartum bleeding complications cannot be predicted with certainty, neither by past history of bleeding episodes or haematological laboratory tests of VWF activity levels. Hence, in all patients factor VIII-VWF concentrate replacement therapy should be initiated already in the first stage of labour. Post partum replacement therapy along with effective uterotonic therapy should be continued at least for seven days. With this treatment bleeding problems may be largely prevented. The decision to perform epidural block in labour and delivery must be assessed depending on individual risk factors.

Adult↗