Initiation Of Oral Anticoagulant Therapy Research Articles

Is there a hypercoagulable phase during initiation of antithrombotic therapy with oral anticoagulants in patients with atrial fibrillation?

Introduction: During commencement of oral anticoagulant therapy (OAT) a theoretical possibility of a transient hypercoagulable state emerges from the difference in plasma half-life between the vitamin K-dependent pro-coagulation factors II and X, and the vitamin K-dependent anticoagulant proteins C and S. In the present study, markers reflecting the activity in the haemostatic system (prothrombin fragment 1+2 [F1+2], d-dimer and soluble fibrin) was assessed during initiation of OAT compared to subcutaneously administered low-molecular weight heparin (LMWH) which does not cause any imbalance between the concentrations of the pro- and anticoagulation proteins. Methods: Thirty-three patients with atrial fibrillation were randomly treated either with OAT (warfarin 10, 7.5, and 5 mg for three consecutive days) or LMWH administered in a fixed dose of 200 anti-Xa IU/kg body weight in one subcutaneous injection daily. The biochemical markers were measured at baseline, and after 12, 36 and 60 h of treatment. Results and conclusions: After introducing antithrombotic therapy, none of the biochemical markers increased within the study period in the two treatment groups. The level of F1+2 had declined significantly at 60 h in both groups. The level of soluble fibrin showed a significant decrease within the first 60 h in the OAT group, and no significant changes were seen in the LMWH group. No significant change in the level of d-dimer was seen during the first 60 h of treatment in either group. Taken together, no transient hypercoagulable state could be identified within the first 60 h of commencing OAT in patients with atrial fibrillation.

Prospective Assessment of a Nomogram for the Initiation of Oral Anticoagulation Therapy for Outpatient Treatment of Venous Thromboembolism

Venous thromboembolism is a common medical problem. Recently, the emphasis has been on a switch to outpatient low molecular weight heparin therapy. Previous warfarin nomograms have been developed only for inpatients. We prospectively assessed a warfarin initiation nomogram in 105 consecutive outpatients; the nomogram requires International Normalized Ratio (INR) testing on only days 3, 5, and 8. Eighty-three percent had a therapeutic INR by day 5 and 98% by day 8. There were no major bleeds and only 6 instances of INR >4.5. This outpatient warfarin nomogram appears to be safe and efficacious in obtaining timely therapeutic levels of warfarin and deserves further study.

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

Coumarin-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-intensity and low-intensity coumarin therapy. In addition, f1.2, TAT, activated F VII (F VIIa) and the activities of F II, 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 VIIa 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 f1.2 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.

Livedo Vasculitis With Protein C System Deficiency

To the Editor.— Protein C is a vitamin K—dependent plasma glycoprotein synthetized in the liver. Thrombomodulin (the endothelial receptor for thrombin) catalyzes the thrombin activation of protein C. Activated protein C has anticoagulant activity. Protein C deficiency is responsible for a hypercoagulable state that can be symptomatic. 1 Protein C deficiency is either acquired or is transmitted in an autosomal dominant fashion. 1 Homozygous deficiency is responsible for neonatal purpura fulminans and disseminated intravascular coagulation within the first days of life. Heterozygous deficiency is responsible for deep-vein thrombosis in young adults. Development of skin necrosis in these patients during the initiation of oral anticoagulant therapy is also well known. It is probably caused by a rapid drop in protein C concentration, which has a shorter life than most of the procoagulant vitamin K—dependent factors, thus resulting in a transient hypercoagulable state. We report a case of livedo reticularis with superficial

Monitoring prothrombin fragment 1 + 2 during initiation of oral anticoagulant therapy after intracoronary stenting.

Patients with intracoronary stent implantation are treated with aggressive anticoagulant and antiplatelet therapy consisting of high-dose heparin, phenprocoumon, acetylsalicylic acid, dipyridamole, and the infusion of dextran to prevent a subacute thrombotic occlusion of the stented segment. In an effort to optimize this treatment by reducing both imminent bleeding complications and subacute thrombotic occlusion, the concentrations of prothrombin fragment 1 + 2 (F 1 + 2) were determined after intracoronary Palmaz-Schatz stent implantation in 19 consecutive patients. The F 1 + 2 concentrations after stent implantation and before the initiation of oral anticoagulant therapy (OAT) were 0.35 nm/l and 0.25-0.53 nm/l (median and 25th-75th percentile), versus 0.74 nm/l and 0.52-0.78 nm/l, in healthy subjects and 0.61 nm/l and 0.30-1.02 nm/l in 15 patients with ongoing proximal DVT. Nine days after initiation of OAT, F 1 + 2 concentrations in both patient groups had not yet reached levels observed in patients with OAT in the stable state (0.16 nm/l, 0.12-0.26 nm/l; n = 76; P less than 0.0001 compared with healthy subjects; INR 2.0-4.5). Despite an INR greater than 2.0, accompanying heparinization was terminated on day 9. In two stented patients a minor bleeding complication arose after the removal of the arterial catheter. Subacute thrombotic occlusions were not observed. Since F 1 + 2 concentrations did not exceed the upper limit of normal range (1.11 nm/l) in any of the 19 patients, the therapeutic regimen was not changed. Monitoring F 1 + 2 may thus be helpful in introducing a more individual treatment if aggressive anticoagulation has to be performed.

Coumarin Necrosis, Neonatal Purpura Fulminans, and Protein C Deficiency

Protein C (PC), a 62,000-molecular weight vitamin K-dependent serine protease zymogen, is a natural anticoagulant that occurs in plasma at 4 mg/L. Activated PC inactivates clotting factors V and VIII and is also profibrinolytic. Activated PC is enhanced in its anticoagulant activity by protein S (PS), another vitamin K-dependent protein. Protein S is found in platelets and endothelial cells as well as in plasma. Inherited PC deficiency and PS deficiency have been associated with venous thrombosis. Both heterozygous PC and PS deficiency appear to be inherited in an autosomal dominant manner in some families. Homozygous PC deficiency presents as neonatal purpura fulminans and results in massive venous thrombosis of the skin and other organs within the first few days of life. Symptomatic heterozygous PC deficiency and PS deficiency have been treated with oral anticoagulants, successfully minimizing recurrence of thrombosis. Coumarin-induced skin necrosis, a rare complication of oral anticoagulant therapy usually seen within three to five days of initiation of therapy, has also been associated with heterozygous PC deficiency. The short half-life of PC (six to eight hours) compared with most of the vitamin K-dependent clotting factors (greater than 30 hours) is the probable reason for this paradoxical response to oral anticoagulants in some PC-deficient patients, since a transient imbalance of procoagulant and anticoagulant factors may exist during initiation of oral anticoagulant therapy. Acquired deficiency of the PC pathway occurs in disseminated intravascular coagulation and possibly other diseases such as those associated with a lupus anticoagulant.