Successful Progressive Anticoagulation in a Severe Protein C Deficiency and Previous Skin Necrosis at the Initiation of Oral Anticoagulant 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there was an unexpectedly slow return of PC activity and antigen to normal levels after the oral anticoagulant was withdrawn (levels were still below normal on day 4).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.

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

10.1055/s-0038-1644286 ◽

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.

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Protein C response to induction and withdrawal of oral anticoagulant treatment

Clinical & Laboratory Haematology ◽

10.1111/j.1365-2257.1987.tb00089.x ◽

1987 ◽

Vol 9 (3) ◽

pp. 255-262 ◽

Cited By ~ 6

Author(s):

K. P. SCHOFIELD ◽

JEAN M. THOMSON ◽

L. POLLER

Keyword(s):

Oral Anticoagulant ◽

Protein C ◽

Anticoagulant Treatment ◽

Oral Anticoagulant Treatment

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Oral Anticoagulant Treatment with and without Aspirin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642729 ◽

1995 ◽

Vol 74 (01) ◽

pp. 506-510 ◽

Cited By ~ 11

Author(s):

Raul Altman ◽

Jorge Rouvier ◽

Enrique Gurfinkel

Keyword(s):

Oral Anticoagulant ◽

Anticoagulant Treatment ◽

Oral Anticoagulant Treatment

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

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656064 ◽

1997 ◽

Vol 77 (05) ◽

pp. 0839-0844 ◽

Cited By ~ 34

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.

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

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656034 ◽

1997 ◽

Vol 77 (04) ◽

pp. 685-689 ◽

Cited By ~ 11

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.

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