Inhibition rather than Enhancement of Hemostatic System Activation during Initiation of Oral Anticoagulant Treatment

1997 ◽  
Vol 77 (04) ◽  
pp. 685-689 ◽  
Author(s):  
Paul A Kyrle ◽  
Johannes Brockmeier ◽  
Ansgar Weltermann ◽  
Sabine Eichinger ◽  
Wolfgang Speiser ◽  
...  
Keyword(s):  
High Intensity ◽  
Oral Anticoagulant ◽  
Protein C ◽  
Venous Blood ◽  
Rapid Decline ◽  
Oral Anticoagulant Treatment ◽  
Shed Blood ◽  
Low Intensity ◽  
Hemostatic System ◽  
System Activation

SummaryCoumarin-induced skin necrosis is believed to be due to a transient hypercoagulable state resulting from a more rapid decline of the protein C activity relative to that of coagulation factors (F) II, IX and X during initiation of oral anticoagulant therapy. We studied hemostatic system activation during early oral anticoagulant treatment with a technique that investigates coagulation activation in the microcirculation.We determined in 10 healthy volunteers the concentrations of prothrombin fragment F1+2 (f1.2) and thrombin-antithrombin complex (TAT) in blood emerging from an injury of the microvasculature (bleeding time incision) before and after initiation of both high-inten- sity and low-intensity coumarin therapy. In addition, f1.2, TAT, activated F VII (F Vila) and the activities of FII, F VII, F X and protein C were measured in venous blood.A rapid decline of F VII and protein C was observed in venous blood with activities at 24 h of 7 ± 1% and 43 ± 2%, respectively, during the high-intensity regimen. A 20 to 30% reduction of f1.2 and TAT was seen in venous blood at 72 h with no major difference between the high- and the low-intensity regimen. F Vila levels were substantially affected by anticoagulation with a >90% reduction at 48 h during the high-intensity regimen. Following high-intensity coumarin, a >50% decrease in the fl.2 and TAT levels was found in shed blood at 48 h suggesting substantial inhibition of thrombin generation during early oral anticoagulation. An increase in the f1.2 and TAT levels was seen neither in shed blood nor in venous blood.Our data do not support the concept of a transient imbalance between generation and inhibition of thrombin as the underlying pathomechanism of coumarin-induced skin nekrosis.

A Comparison of a Moderate with Moderate-high Intensity Oral Anticoagulant Treatment in Patients with Mechanical Heart Valve Prostheses

1997 ◽  
Vol 77 (05) ◽  
pp. 0839-0844 ◽  
Author(s):  
Vittorio Pengo ◽  
Fabio Barbero ◽  
Alberto Banzato ◽  
Elisabetta Garelli ◽  
Franco Noventa ◽  
...  
Keyword(s):  
Heart Valve ◽  
High Intensity ◽  
Oral Anticoagulant ◽  
Oral Anticoagulants ◽  
Mechanical Heart Valve ◽  
Moderate Intensity ◽  
Minor Bleeding ◽  
Anticoagulant Treatment ◽  
Oral Anticoagulant Treatment ◽  
Valve Prostheses

SummaryBackground. The long-term administration of oral anticoagulants to patients with mechanical heart valve prostheses is generally accepted. However, the appropriate intensity of oral anticoagulant treatment in these patients is still controversial.Methods and Results. From March 1991 to March 1994, patients referred to the Padova Thrombosis Center who had undergone mechanical heart valve substitution at least 6 months earlier were randomly assigned to receive oral anticoagulants at moderate intensity (target INR = 3) or moderate-high intensity (target INR = 4). Principal end points were major bleeding, thromboembolism and vascular death. Minor bleeding was a secondary end-point.A total of 104 patients were assigned to the target 3 group and 101 to the target 4 group; they were followed for from 1.5 years to up 4.5 years (mean, 3 years). Principal end-points occurred in 13 patients in the target 3 group (4 per 100 patient-years) and in 20 patients in the target 4 group (6.9 per 100 patient-years). Major hemorrhagic events occurred in 15 patients, 4 in the target 3 group (1.2 per 100 patient-years) and 11 in the target 4 group (3.8 per 100 patient-years) (p = 0.019). The 12 recorded episodes of thromboembolism, 4 of which consisted of a visual deficit, were all transient ischemic attacks, 6 in the target 3 group (1.8 per 100 patient-years) and 6 in the target 4 group (2.1 per 100 patient- years). There were 3 vascular deaths in each group (0.9 and 1 per 100 patient-years for target 3 and target 4 groups, respectively). Minor bleeding episodes occurred 85 times (26 per 100 patient-years) in the target 3 group and 123 times (43 per 100 patient-years) in the target 4 group (p = 0.001).Conclusions. Mechanical heart valve patients on anticoagulant treatment who had been operated on at least 6 months earlier experienced fewer bleeding complications when maintained on a moderate intensity regimen (target INR = 3) than those on a moderate-high intensity regimen (target INR = 4). The number of thromboembolic events and vascular deaths did not differ between the two groups.

PROTEIN C RESPONSE TO INDUCTION AND WITHDRAWAL OF ORAL ANTICOAGULANT TREATMENT

1987 ◽  
Author(s):  
K P Schofield ◽  
J M Thomson ◽  
L Poller
Keyword(s):  
Oral Anticoagulant ◽  
Protein C ◽  
Oral Anticoagulants ◽  
Factor Vii ◽  
Factor X ◽  
Anticoagulant Treatment ◽  
Oral Anticoagulant Treatment ◽  
Rate Of Increase ◽  
Long Term Treatment

Protein C (PC) activity and antigen levels have been related to clotting activities of factors VII and X during the induction and withdrawal periods of oral anticoagulant treatment. Both factor VII and PC activities fell rapidly during a gradual induction regime of nicoumalone in six consecutive patients but factor VII showed a more rapid and much more marked depression than PC. In contrast reductions in factor X were much slower. PC antigen although depressed rapidly at the initiation of treatment did not subsequently fall to the same degree as PC activity, The ratio of activity to antigen became progressively smaller.In six further serial patients discontinued from long-term treatment with nicoumalone (mean duration 12-6 months) there was a reversal of the pattern, but with two important differences. Firstly, there was evidence of an excessive rise (“rebound”) of factor VII compared with the steady state levels in these patients; and secondly there was an unexpectedly slow return of PC activity and antigen to normal levels after the oral anticoagulant was withdrawn (levels were still below normal on day 4). Factor X also showed a slow rate of increase, similar to PC activity recovery. These observations lend support to gradual withdrawal of oral anticoagulants after a period of long-term administration. The results suggest that after discontinuation of long-term oral anticoagulants patients may have increased coagulability up to four days.

ANTICOAGULANT AND ANTIGENIC LEVELS OF PROTEIN C AND PROTEIN S IN PATIENTS ON STABILIZED ORAL ANTICOAGULANT TREATMENT

1987 ◽  
Author(s):  
A D'Angelo ◽  
F Gilardoni ◽  
M P Seveso ◽  
P Poli ◽  
R Quintavalle ◽  
...  
Keyword(s):  
Vitamin K ◽  
Oral Anticoagulant ◽  
Protein C ◽  
Protein S ◽  
Reference Interval ◽  
Factor Ix ◽  
Activity Levels ◽  
Anticoagulant Treatment ◽  
Oral Anticoagulant Treatment ◽  
Congenital Deficiency

Isolated deficiencies of protein C and protein S, two vitamin K-dependent plasma proteins, constitute about 70% of the congenital abnormalities of blood coagulation observed in patients with recurrent venous thrombosis beLow the age of 40. The laboratory diagnosis of congenital deficiency of these proteins represents a major problem since a large proportion of patients are on oral anticoagulation (OA) at the time the deficiencies are suspected.Under these circumstances the availability of a reference interval obtained in patients on stabilized OA has proven useful.Functional (C) and antigenic levels (Ag) of protein C, protein S, factor IX and II were estimated in 136 patients on stabilized OA, subdivided according to the degree of anticoagulation (Internatio nal Normalized Ratio, INR).The results indicate that with increasing anticoagulation the activity levels of all the vitamin K-dependent factors decrease to a greater extent than the corresponding antigenic levels. At variance with the other factors, total protein S antigen levels are only moderately reduced by OA with protein S anticoagulant activi ty comparing well to factor IX clotting activity. These data suggest the possibility of identifying both quantitative and qualita tive deficiencies of protein C and protein S in patients on oral anticoagulant treatment.

Prevention of thromboembolism in patients with mitral stenosis and associated atrial fibrillation: effectiveness of low intensity (INR target 2) oral anticoagulant treatment

2003 ◽  
Vol 89 (04) ◽  
pp. 760-764 ◽  
Author(s):  
Fabio Barbero ◽  
Alessandra Biasiolo ◽  
Cinzia Pegoraro ◽  
Franco Noventa ◽  
S. Iliceto ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
High Risk ◽  
Major Bleeding ◽  
Mitral Stenosis ◽  
Oral Anticoagulant ◽  
Moderate Intensity ◽  
Anticoagulant Treatment ◽  
Systemic Embolism ◽  
Oral Anticoagulant Treatment ◽  
Low Intensity

SummaryMitral stenosis (MS) in association with atrial fibrillation (AF) is a clinical condition at high risk for systemic thromboembolism. Although oral anticoagulants greatly reduce the incidence of thromboembolism in these patients, the optimal intensity of treatment has never been tested in specific clinical trials, and current recommendations are derived from studies of nonrheuma-tic AF. In this study we tested the effectiveness of two different intensities. The study design was carried out as an open randomized prospective study in an anticoagulation clinic.We randomized 103 patients with MS and AF to a low (target INR = 2) or moderate (target INR = 3) anticoagulation regimen. The primary end points were systemic thromboembolism, major bleeding and vascular death.During a mean follow-up of 4.5 years, 1 systemic embolism occurred in the low intensity group (0.41 per 100 pt/yrs, CI 0.01-2.3), and 1 minor stroke occurred in the moderate intensity group (0.40 per 100 pt/yrs, CI 0.01-2.3; p = ns). Major bleeding occurred in 8 patients, with 3 in the low intensity (1.25 per 100 pt/yrs) and 5 in the moderate intensity group (2.0 per 100 pt/yrs, Incidence Rate Ratio 0.6, CI 0.1-3.1; p = ns). Total events (systemic embolism, major bleeding and vascular death) occurred in 7 low intensity patients and 8 moderate intensity patients. As expected, minor bleeding was more frequent in the moderate intensity group of patients, who actually had more intense treatment and required closer monitoring of oral anticoagulant treatment.These data suggest that low intensity anticoagulation, as performed in an anticoagulation clinic, is effective and safe in high risk patients with MS and AF.

Comparison of the Effects of Different Low Molecular Weight Heparins on the Hemostatic System Activation In Vivo in Man

1997 ◽  
Vol 78 (02) ◽  
pp. 876-879 ◽  
Author(s):  
Michael Wolzt ◽  
Michaela Eder ◽  
Ansgar Weltermann ◽  
Jesusa Entlicher ◽  
Hans-Georg Eichler ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Venous Blood ◽  
Plasma Concentrations ◽  
Low Molecular Weight ◽  
Double Blind ◽  
Shed Blood ◽  
Hemostatic System ◽  
Activated State ◽  
A Minor

SummaryIn a double-blind, randomized, cross-over study the effects of single subcutaneous doses of 120 anti-Xa units/kg body wt. of three different low molecular weight heparin (LMWH) preparations were investigated in 15 healthy subjects by determination of thrombin-antithrombin El complex (TAT), prothrombin fragment 1.2 (fl.2), and β-thromboglobin (β-TG) in shed blood and in venous blood.Certoparin, dalteparin, and enoxaparin significantly inhibited coagulation activation marker formation in shed blood. The substantial inhibition of TAT and fl.2 formation was slightly more pronounced in response to certoparin. β-TG was decreased following certoparin and enoxaparin, but not following dalteparin. However, no difference between groups was detectable. A small but consistent decrease of fl.2 formation in venous blood was noted for all LMWHs and dalteparin and enoxaparin, but not certoparin, inhibited TAT formation. Only a minor impact of the three LMWH preparations was noted on β-TG plasma concentrations.Our data indicate that the studied LMWH preparations have a major impact on blood clotting in the activated state and inhibit in vivothe hemostatic system to a comparable extent.

Effect of Exercise Modality and Intensity on Postexercise Interleukin-6 and Hepcidin Levels

2013 ◽  
Vol 23 (2) ◽  
pp. 178-186 ◽  
Author(s):  
Marc Sim ◽  
Brian Dawson ◽  
Grant Landers ◽  
Dorine W. Swinkels ◽  
Harold Tjalsma ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
High Intensity ◽  
Serum Iron ◽  
Iron Status ◽  
Venous Blood ◽  
Exercise Modality ◽  
Low Intensity ◽  
High Intensity Interval ◽  
Interval Cycling ◽  
Continuous Running

The effect of exercise modality and intensity on Interleukin-6 (IL-6), iron status, and hepcidin levels was investigated. Ten trained male triathletes performed 4 exercise trials including low-intensity continuous running (L-R), low-intensity continuous cycling (L-C), high-intensity interval running (H-R), and high-intensity interval cycling (H-C). Both L-R and L-C consisted of 40 min continuous exercise performed at 65% of peak running velocity (vVO2peak) and cycling power output (pVO2peak), while H-R and H-C consisted of 8 × 3-min intervals performed at 85% vVO2peak and pVO2peak. Venous blood samples were drawn pre-, post-, and 3 hr postexercise. Significant increases in postexercise IL-6 were seen within each trial (p < .05) and were significantly greater in H-R than L-R (p < .05). Hepcidin levels were significantly elevated at 3 hr postexercise within each trial (p < .05). Serum iron levels were significantly elevated (p < .05) immediately postexercise in all trials except L-C. These results suggest that, regardless of exercise mode or intensity, postexercise increases in IL-6 may be expected, likely influencing a subsequent elevation in hepcidin. Regardless, the lack of change in postexercise serum iron levels in L-C may indicate that reduced hemolysis occurs during weight-supported, low-intensity activity.

The effect of ß-receptor blockade on factor VIII levels and thrombin generation in patients with venous thromboembolism

2003 ◽  
Vol 89 (05) ◽  
pp. 837-841 ◽  
Author(s):  
Verena Schönauer ◽  
Sandra Giannini ◽  
Günter Christ ◽  
Peter Quehenberger ◽  
Christian Bieglmayer ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Factor Viii ◽  
Venous Blood ◽  
Skin Incision ◽  
Receptor Blockade ◽  
Shed Blood ◽  
Increased Risk ◽  
History Of ◽  
System Activation ◽  
Β Receptor

SummaryHigh factor VIII (FVIII) is a risk factor for venous thromboembolism (VTE). The pathomechanism by which high FVIII leads to an increased risk of VTE is unknown. Physical activity and infusion of adrenalin provoke a rise in FVIII, which can be blocked by a nonselective β-blockade. We tested the hypothesis that in patients with a VTE β-blockade decreases FVIII and inhibits coagulation activation.17 male patients with high FVIII (> 170 IU/dL, n = 7) or low FVIII (<150 IU/dL, n = 10) and a history of VTE received 40 mg of propranolol thrice daily for 14 days. FVIII and vasopressin levels were measured before and during propranolol intake and 28 days thereafter. At the same time points, haemostatic system activation was investigated by measuring prothrombin fragment f1.2 (f1.2) and thrombin antithrombin complexes (TAT) in venous blood and in blood emerging from a skin incision (shed blood).The mean FVIII level before propranolol was 192 IU/dL and 115 IU/dL in patients with high and low FVIII, respectively. During and 28 days after propranolol, no significant change in FVIII was seen in both groups. Changes in f1.2 and TAT were not detectable in either venous blood or in shed blood.β-receptor blockade did not lower FVIII or inhibit haemostatic system activation in patients with VTE and persistently high FVIII. Administration of propranolol cannot be recommended as secondary thromboprophylaxis in patients with high FVIII.

Lower versus standard intensity oral anticoagulant therapy (OAT) in elderly warfarin-experienced patients with non-valvular atrial fibrillation

2010 ◽  
Vol 103 (02) ◽  
pp. 442-449 ◽  
Author(s):  
Umberto Cucchini ◽  
Gentian Denas ◽  
Bruce Davidson ◽  
Filippo Marzot ◽  
Seena Padayattil Jose ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Elderly Patients ◽  
Oral Anticoagulant ◽  
Oral Anticoagulant Therapy ◽  
Anticoagulation Therapy ◽  
Bleeding Risk ◽  
Nonvalvular Atrial Fibrillation ◽  
Oral Anticoagulant Treatment ◽  
Low Intensity ◽  
Standard Intensity

SummaryIt has been observed that elderly patients with nonvalvular atrial fibrillation (NVAF) benefit from standard [an international normalised ratio (INR) goal of 2.0–3.0] oral anticoagulant treatment (OAT). The hypothesis that lower-intensity anticoagulation therapy can offset the higher bleeding risk in this population has never been tested in an ‘ad hoc’ clinical trial. Patients over 75 years of age with NVAF were randomised to receive warfarin to maintain the INR at 1.8 (range 1.5–2.0) or at a standard target of 2.5 (range 2.0–3.0). There were 135 patients in the low-intensity and 132 in the standard-intensity groups. During a mean follow-up lasting 5.1 years, 59 primary outcome events (thromboembolism and major haemorrhage) were recorded, 24 (3.5 per 100 patient-years) in the low-intensity group and 35 (5.0 per 100 patient-years) in the standard-intensity group (HR=0.7, 95% CI 0.4–1.1, p=0.1). The reduction in the primary endpoint was mainly due to a diminution in major bleedings (1.9 vs. 3.0 per 100 patient-years; HR=0.6, 95% CI 0.3–1.2, p=0.1). The median achieved INR value was 1.86 in the low-intensity and 2.24 in the standard-intensity group (p<0.001). The frequency of INR testing was 26.1 ± 13.5 vs. 24.3 ± 11.6 days, p<0.0001). In this exploratory study we observed a low rate of stroke and major bleeding in elderly patients (>75) being managed in an anticoagulation clinic for primary stroke prevention with low-intensity anticoagulation (INR 1.5–2.0). However, further trials are needed to confirm the hypothesis generated by the present study.

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