Long-term treatment with sodium warfarin results in decreased femoral bone strength and cancellous bone volume in rats.

The issue of whether long-term sodium warfarin therapy results in decreased bone density is controversial. To address this question, we randomized rats to once daily subcutaneous injections of either sodium warfarin (0.20 or 0.

Like fibrin, (DD)E, the major degradation product of crosslinked fibrin, protects plasmin from inhibition by alpha2-antiplasmin.

Plasmin generation is localized to the fibrin surface because tissue-type plasminogen activator (t-PA) and plasminogen bind to fibrin, an interaction that stimulates plasminogen activation over a hundred-fold. To ensure efficient fibrinolysis, plasmin bound to fibrin is protected from inhibition by alpha2-antiplasmin. (DD)E, a major soluble degradation product of cross-linked fibrin that is a potent stimulator of t-PA, compromises the fibrin-specificity of t-PA by promoting systemic activation of plasminogen.

Exosites 1 and 2 are essential for protection of fibrin-bound thrombin from heparin-catalyzed inhibition by antithrombin and heparin cofactor II.

Assembly of ternary thrombin-heparin-fibrin complexes, formed when fibrin binds to exosite 1 on thrombin and fibrin-bound heparin binds to exosite 2, produces a 58- and 247-fold reduction in the heparin-catalyzed rate of thrombin inhibition by antithrombin and heparin cofactor II, respectively. The greater reduction for heparin cofactor II reflects its requirement for access to exosite 1 during the inhibitory process. Protection from inhibition by antithrombin and heparin cofactor II requires ligation of both exosites 1 and 2 because minimal protection is seen when exosite 1 variants (gamma-thrombin and thrombin Quick 1) or an exosite 2 variant (Arg93 --> Ala, Arg97 --> Ala, and Arg101 --> Ala thrombin) is substituted for thrombin.

Perioperative management of long-term anticoagulation.

When the need for surgery arises, temporary interruption of long-term anticoagulation exposes patients to additional thrombotic risk. There is no consensus as to how perioperative anticoagulation should be managed in this setting. Based on an individual assessment of risk factors for arterial or venous thromboembolism and the risk of postoperative bleeding, this review outlines an approach to the perioperative management of anticoagulation that is designed to optimize patient safety and efficient delivery of health care.

Direct thrombin inhibitors for treatment of arterial thrombosis: potential differences between bivalirudin and hirudin.

Given the central role of thrombin in arterial thrombogenesis, most treatment strategies for acute coronary syndromes are aimed at inhibiting its generation or blocking its activity. Although heparin has been widely used, it has limitations in the setting of arterial thrombosis. These limitations reflect the inability of heparin to inactivate thrombin bound to fibrin, a major stimulus for thrombus growth.

Hirudin causes more bleeding than heparin in a rabbit ear bleeding model.

This study was undertaken to determine the appropriateness of the current practice of using the activated partial thromboplastin time (APTT) to select hirudin doses. A rabbit bleeding ear model was used to compare the effects of various doses of heparin and hirudin on the relationship between the APTT and bleeding. In addition, the effects of these agents on the thrombin clotting time (TCT) and factor Xa clotting time also were examined.

Polypeptide-polysaccharide conjugates produced by spontaneous non-enzymatic glycation.

A fundamental dogma has developed over the past 20 years that non-enzymatic glycation involving saccharide chains of greater than 3 to 4 residues is an extremely unlikely reaction. Our investigations using glycosaminoglycans have shown that, given sufficient time, polypeptide-polysaccharide conjugates form via the Schiff base-Amadori rearrangement mechanism. Further, even though these straight chain polysaccharides are relatively charged and sterically hindered, spontaneous glycation can also occur in vivo.

Thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparin-antithrombin but susceptible to inactivation by antithrombin-independent inhibitors.

Background: Thrombolytic therapy induces a procoagulant state characterized by elevated plasma levels of fibrinopeptide A (FPA), but the responsible mechanism is uncertain.

Methods And Results: Washed plasma clots were incubated in citrated plasma in the presence or absence of tissue plasminogen activator (t-PA), and FPA generation was monitored as an index of unopposed thrombin activity. FPA levels are almost twofold higher in the presence of t-PA than in its absence.