Tatsuhiko Takahama

Anticoagulation during use of a left ventricular assist device.

Thirty-six mongrel dogs underwent 24hr left ventricular assist. The VAD was placed between the left atrium and the descending aorta, and the dogs were divided into four groups according to type of anticoagulation: no anticoagulation, argatroban, nafamostat mesylate, and nafamostat mesylate + prostacyclin analog. Results of this animal experiment revealed that a newly developed synthetic thrombin inhibitor argatroban can prevent activation of the intrinsic coagulation pathway. Argatroban is efficient under any blood coagulative condition, even lack of anti-thrombin III, because of its direct inhibitory effect on thrombin, making argatroban more useful than heparin as an anticoagulant for LVAD. Argatroban, as well as heparin, provides marked and significant prolongation of the prothrombin time from early assisted circulation, but produces a bleeding tendency. Nafamostat mesylate can maintain blood coagulation parameters within the acceptable range. Combined administration of nafamostat mesylate and a prostacyclin analog cause the least decrease in fibrinogen and alpha2-plasmin inhibitor among the four groups and causes no significant prolongation of prothrombin time.

Significance of various anticoagulation therapies during use of a left ventricular assist device.

A multicomparative study to establish adequate anticoagulation therapy for left ventricular assist devices was undertaken by administrating various anticoagulants: heparin, a prostacyclin analogue combined with a protease inhibitor; thromboxane A2 synthetase inhibitor; or a protease inhibitor alone. Our investigation suggested that combined administration of prostacyclin analogue and protease inhibitor (FUT-175) is ideal anticoagulation therapy from the point of blood coagulation and fibrinolysis. Currently, however, sole administration of FUT-175 is adequate anticoagulation therapy during clinical use of left ventricular assist devices.

Ideal anticoagulation for use with a left ventricular assist device.

To establish ideal anticoagulation therapy for use with a left ventricular assist device, a study was done administering various anticoagulants: heparin, argatroban, a prostacyclin analogue combined with a protease inhibitor, or a protease inhibitor alone. Cardiac asisting by LVAD without any anticoagulants results in marked activation of blood coagulation or fibrinolysis. Administration of argatroban, as well as heparin, produces a bleeding tendency. Administration of a protease inhibitor (nafamostat mesilate, FUT-175) as a sole anticoagulant induces activation of the blood coagulation system to some extent, but it is within acceptable limits. Combined administration of a prostacyclin analogue (PG) and FUT-175 is most effective in maintaining balanced blood coagulation and fibrinolysis.

Pharmacodynamics of FUT-175 anticoagulant in adsorbent plasma perfusion.

FUT, a new synthetic protease inhibitor, has been used recently in hemodialysis as an anticoagulant in patients with bleeding tendencies. As some new adsorbents require alternatives to heparin because of their strong adsorbing capacity for heparin, plasma perfusion with FUT anticoagulation was pharmacodynamically investigated. Blood was pumped from a dog (QB = 50-70 ml/min) into a plasma separator. The separated plasma (QP = 10-20 ml/min) passed through an adsorbent column and was reinfused into the blood that had passed through the plasma separator. FUT was continuously infused, at a flow rate of 50 mg/hr, into the blood as it left the dog and entered the extracorporeal circuit. Blood and plasma samples were taken as it exited the dog (S1), before and after the adsorbent column (S2, S3), and before reinfusion into the dog (S4). Except for that done with a charcoal-column, adsorbent plasma perfusion went well and the dog tolerated the procedure. FUT levels in S2, S3, and S4 provided anticoagulation. However, as the FUT levels in S1 remained negligible, the dogs coagulation time was within normal limits. In conclusion, FUT was pharmacodynamically proven to be a safe and reasonable anticoagulant for adsorbents that adsorb large amounts of heparin and for patients with bleeding tendencies.

A new improved biodegradable tracheal prosthesis using hydroxy apatite and carbon fiber.

A new biodegradable tracheal prosthesis was developed using hydroxyapatite rings as the artificial tracheal cartilage, a carbon fiber tube as the tracheal tube; it was then implanted into the cervical trachea in dogs. Morphologic examination revealed that the hydroxyapatite ring was anchored firmly to the tracheal cartilage by ingrowth of cartilaginous tissue into the macropores of the hydroxyapatite.

Danger of urokinase as an anticoagulant with left ventricular assist devices.

The sole administration of urokinase causes no initial prolongation of activated partial thromboplastin time (A-PTT), but thereafter produces serious progressive prolongation of A-PTT; it also causes a progressive, severe decrease in fibrinogen levels and alpha 2-plasmin inhibitor activity by depletion. The antithrombogenicity of urokinase is not caused by prevention of blood coagulation system activation by antithrombin effect, but by secondary fibrinolysis by plasmin. Consequently, the administration of urokinase as a sole anticoagulant results in activation of coagulation and fibrinolysis, and, as a result, induces disseminated intravascular coagulation. Therefore, it is concluded that administration of urokinase is an inadequate anticoagulation therapy unless it is combined with other antithrombin agents.

A thromboxane A2 synthetase inhibitor as an anticoagulant for left ventricular assist devices.

A comparative study to establish more adequate anticoagulation therapy for left ventricular assist devices was done by administering various anticoagulants: heparin, argatroban (a pure thrombin inhibitor), a thromboxane A2 synthetase inhibitor, and protease inhibitor. Results of the investigation revealed that use of no anticoagulation activates the intrinsic pathway of blood coagulation and causes severe coagulopathy, heparin or argatroban causes bleeding tendency, and a thromboxane A2 synthetase inhibitor can maintain blood coagulation within the acceptable range, but not completely. Combined administration of a throm.