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G Cvirn

Publications and source records attributed to G Cvirn.

11 recordsLinked to original sources
PubMed2006

Thrombin generation in factor VIII-depleted neonatal plasma: nearly normal because of physiologically low antithrombin and tissue factor pathway inhibitor.

BACKGROUND: Bleeding in hemophilic neonates has a low incidence. A possible explanation for this could be the peculiarities of the neonatal hemostatic system, especially low levels of the inhibitors tissue factor pathway inhibitor (TFPI) and antithrombin (AT). OBJECTIVE: We investigated the influence of an elevation of these inhibitors to adult levels on the thrombin generation (TG) in normal neonatal plasma and factor (F) VIII-depleted neonatal plasma by means of incubation with anti-FVIII-antibodies. PATIENTS/METHODS: TG was measured after activation with low amounts of tissue factor (TF) by using Calibrated Automated Thrombography. RESULTS: TG in FVIII-depleted neonatal plasma was nearly as high as in normal neonatal plasma. TG decreased after elevation of AT in both neonatal plasmas. After elevation of TFPI TG decreased much more in FVIII-depleted neonatal plasma than in normal neonatal plasma. After elevation of both inhibitors their synergistic effect led to a stronger decrease of TG in FVIII-depleted neonatal plasma. TG measured in plasma of one hemophilic newborn showed the same pattern as in FVIII-depleted neonatal plasma. CONCLUSION: Our observation provides a biochemical basis for the rare bleeding in hemophilic neonates and shows the important role of the natural inhibitors in the hemostatic system of hemophilic patients.

Adult↗
PubMed2003

Low tissue factor pathway inhibitor (TFPI) together with low antithrombin allows sufficient thrombin generation in neonates.

Neonates have an excellent hemostasis despite, in comparison to adults, markedly decreased and delayed ability to generate thrombin. Only 30-50% of peak adult thrombin activity can be produced in neonatal plasma by means of conventional in vitro assays. We show that in contrast to conventional activation, activation with small amounts of lipidated tissue factor (<10 pmol L(-1)) results in shorter clotting times and faster activated factor X- and thrombin generation in neonates compared with adults due to the concomitant action of low tissue factor pathway inhibitor and antithrombin. The concentrations of both inhibitors in cord plasma are approximately 50% of the respective adult values. After addition of 2.5 pmol L(-1) lipidated tissue factor, cord plasma clotted approximately 90 s earlier than adult plasma and the amount of free thrombin generated was approximately 90% of adult value (291 +/- 14 vs. 329 +/- 16 nmol L(-1) min(-1), P < 0.01). Our results might help to explain the clinically observed excellent hemostasis of neonates despite low levels of procoagulant factors.

Adult↗
PubMed2003

Elevated thrombin-forming capacity of tissue factor-activated cord compared with adult plasma.

Clinically observed excellent hemostasis in neonates despite low levels of clotting factors is not completely understood so far. Therefore, we investigated whether physiological low levels of the inhibitor protein C (PC) facilitate thrombin formation in tissue factor (TF)-activated plasma samples. PC was activated by endogenously generated thrombin after addition of soluble thrombomodulin (TM). The capability of activated PC (APC) to suppress thrombin formation was significantly more pronounced in adult than in cord plasma. Addition of 4 nm of TM decreased the thrombin potential (TP) in cord plasma by 10%, and in adult plasma by 52% in the presence of 5 pm TF. We demonstrate that this low anticoagulant action of PC is attributable to the low levels of tissue factor pathway inhibitor (TFPI) and antithrombin (AT) physiologically present in cord plasma. Addition of 4 nm TM decreased the TP by 58% in cord plasma adjusted to contain TFPI and AT at adult levels in the presence of 5 pm TF. Thus, the combined low anticoagulant action of the three inhibitors APC, TFPI, and AT in cord plasma allows enhanced thrombin formation associated with shorter clotting times compared with adult plasma when low amounts of TF are applied to initiate clot formation. Although our laboratory experiments do not allow definite conclusions for various clinical situations, our data might contribute to explain excellent hemostasis in neonates despite low levels of procoagulants.

Adult↗
PubMed2002

Respective roles of factors II, VII, IX, and X in the procoagulant activity of FEIBA.

Activated prothrombin complex concentrates (APCCs) are effective in the therapy of bleeding episodes in hemophilic patients with inhibitors. We investigated the respective roles of factor II, factor VII, factor IX, and factor X in the procoagulant activity of the APCC FEIBA. Factor II, factor VII, factor IX, and factor X were reduced in platelet-poor plasma, and the thrombin potential (TP) was determined using a chromogenic substrate in the absence or presence of FEIBA. Reduction of factor II resulted in a significant decrease of the TP without influencing the lag phase until the onset of thrombin generation. The reduction of factor VII showed no effect on the TP, but resulted in a prolongation of the lag phase. Changes of factor IX or factor X concentrations showed neither an effect on the TP nor on lag phases. Our study demonstrates that thrombin generation in the presence of FEIBA mainly depends on prothrombin.

Blood Coagulation Factors↗
PubMed2001

Effects of alpha(2)-macroglobulin and antithrombin on thrombin generation and inhibition in cord and adult plasma.

Thromboembolic complications rarely occur during infancy and childhood. It has been reported that increased capacity of cord plasma to inhibit thrombin due to elevated alpha(2)-macroglobulin (alpha(2)-M) levels may in part provide protection from thrombosis. In antithrombin (AT)-deficient plasma, alpha(2)-M exhibits anticoagulant action by complexing substantial amounts of generated free thrombin. It has been suggested that alpha(2)-M has the same impact on thrombin inhibition as AT, the most important thrombin inhibitor in adult plasma. The aim of our study was to examine this assumption by determining time-courses of free thrombin generation and prothrombin activation. Additionally, the amount of thrombin complexed to alpha(2)-M was assessed by comparing the heights of the end-level of amidolytic activity curves (AACs) after extrinsic activation of platelet poor plasma in the presence of different concentrations of AT or alpha(2)-M. Increasing the AT content by 30% resulted in significantly suppressed generation of free thrombin and prothrombin fragment 1+2 (F1+2) in cord and adult plasma. In contrast, increasing the alpha(2)-M content in plasma containing physiologic amounts of AT by the same percentage had no effect on free thrombin generation and on F1+2 generation in both cord and adult plasma. In addition, the effect of AT supplementation on the end-level of the AACs was significantly higher compared to the effect of alpha(2)-M supplementation. Since alpha(2)-M, in contrast to AT, had no effect on free thrombin generation and prothrombin activation, our study suggests that the action between alpha(2)-M and thrombin might not be fast enough to prevent thrombin from its feedback activation in both cord and adult plasma and, therefore, in cord and adult plasma containing physiological amounts of AT alterations of the alpha(2)-M content had no effect on thrombin generation and inhibition.

Adult↗
PubMed2001

Effects of short-term energy restriction and physical training on haemostatic risk factors for coronary heart disease in obese children and adolescents.

OBJECTIVE: To study the changes of haemostatic risk factors for coronary heart disease during a weight reduction programme in obese children and adolescents. DESIGN: A short-term longitudinal study. SUBJECTS: Thirty-seven obese white girls (age, 12+/-1.8 y; body mass index (BMI), 26.9+/-5.25) and 19 obese white boys (age, 11.9+/-1.7 y; BMI, 26.2+/-5.2). MEASUREMENTS: Fibrinogen, factor VII coagulant activity, von Willebrand factor antigen, and soluble P-selectin were determined before and after a 3 week programme including energy restriction and physical activities. RESULTS: All determined haemostatic risk factors decreased significantly during the programme. Changes in risk factors were correlated to changes in body composition. Children and adolescents with the highest initial concentrations showed the greatest decreases. CONCLUSION: Energy restriction combined with physical activity improves the haemostatic risk profile in obese children and adolescents.

Adolescent↗
PubMed2000

Effects of the glycoprotein IIb/IIIa receptor antagonist c7E3 Fab and anticoagulants on platelet aggregation and thrombin potential under high coagulant challenge in vitro.

The present study was performed to investigate the combined effects of the platelet glycoprotein IIb/IIIa receptor antagonist c7E3 Fab (abciximab) and the anticoagulants unfractionated heparin (UH), low molecular weight heparin (LMWH), and recombinant hirudin (rH) on platelet aggregation and thrombin generation under high coagulant challenge by extrinsic activation of platelet-rich plasma. Platelet aggregation and thrombin generation were assessed simultaneously in the presence of different concentrations of abciximab and anticoagulants. Increasing concentrations of abciximab resulted in a dose-dependent anti-aggregating effect with a maximum at 20 microg/ml. Doses of 5, 10, and 20 microg/ml abciximab prolonged the lag phase until the onset of platelet aggregation, but this effect was independent of the dosage used. Abciximab had no influence on the thrombin potential under our high coagulant challenge. UH, LMWH, and rH showed a dose-dependent prolongation of the lag phase until the onset of platelet aggregation and decreased the thrombin potential. Addition of anticoagulants did not contribute to further inhibition of platelet aggregation in the presence of abciximab, but the combination of abciximab and anticoagulants exhibited an additive effect on prolongation of the lag phase until the onset of platelet aggregation. Addition of abciximab to anticoagulants did not result in further decrease of the thrombin potential. Our study demonstrates the respective specific effects of abciximab and anticoagulants on platelet aggregation and thrombin potential under high coagulant challenge, and also an additive effect of abciximab and the anticoagulants UH, LMWH, and rH on the lag phase until the onset of platelet aggregation.

Abciximab↗
PubMed1999

Effects of antithrombin and protein C on thrombin generation in newborn and adult plasma.

It has been suggested that antithrombin (AT) and protein C (PC) might be less important in newborn plasma than in adult plasma for the inhibition of clotting activation. To assess the importance of AT and PC for the regulation of thrombin generation in newborn as compared with adult plasma, thrombin generation was determined in the presence of different concentrations of AT and PC. In both, newborn and adult plasmas, reduction of AT and PC resulted in an increase of thrombin generation after intrinsic activation. On the other hand, supplementation of AT and PC decreased thrombin generation in a dose-dependent manner. Clotting times were influenced by different PC concentrations, whereas clotting times were almost not affected by different amounts of AT. Our study suggests that the significance of AT and PC in the regulation of thrombin generation is the same in newborn and adult plasma. Our experimental results also support the notion that administration of AT or protein C concentrates may be beneficial in some clinical situations leading to an increased clotting activation in newborns.

Adult↗
PubMed1999

Recombinant factor VIIa does not induce hypercoagulability in vitro.

Recombinant factor VIIa (rVIIa) has been reported to be clinically effective and safe in haemophilic patients with inhibitor antibodies. Compared to activated prothrombin complex concentrates the risk of thrombotic complications seems to be very low after rVIIa administration. Determination of free thrombin generation has been shown to identify hypercoagulability. Therefore, free thrombin and prothrombinase activity (Xa generation) were assessed after extrinsic activation of rVIIa supplemented factor VIII and factor IX deficient plasma. Free thrombin generation was also determined after supplementation of (activated) prothrombin complex concentrates. Addition of 150 U rVIIa/ml shortened the clotting times markedly in control, factor VIII, and factor IX deficient plasma. In contrast, free thrombin and Xa generation were not different in the absence or presence of 150 U rVIIa/ml. Addition of (activated) prothrombin complex concentrates resulted in a marked increase of free thrombin generation in all investigated plasmas. Although in vitro studies cannot reflect specific clinical circumstances our results support the notion that rVIIa does not induce a hypercoagulable state as sporadically observed after administration of (activated) prothrombin complex concentrates.

Blood Coagulation↗
PubMedDate not supplied

Alpha-2-macroglobulin inhibits the anticoagulant action of activated protein C in cord and adult plasma.

Healthy newborns have a very low risk of thrombosis. It has been suggested that this is partly due to the anticoagulant effect of alpha-2-macroglobulin (a2-M). This broad-spectrum protease binding glycoprotein is physiologically elevated in newborns over adult values and has been shown to complex generated alpha-thrombin. In our present study, we point out that a2-M also acts as a procoagulant by inhibiting activated protein C (APC). In all experiments performed in cord and adult plasma the anticoagulant action of APC was diminished in a dose-dependent manner when a2-M levels were successively elevated, reflected in increased thrombin potential (TP), and enhanced at low a2-M levels, reflected in decreased TP.

Adult↗