Search
Microvascular Surgery
Making Surgery Safer
Target Condition: Clotting at the site of blood vessel repair
Traditional Approach: Administration of heparin to prevent clot formation
New Approach: Utilizing new blood clot inhibitors
Progress: Several promising compounds are being studied
Investigator Dr. Francis Pelham
An important service to the orthopaedic practitioner is provided by the microvascular specialist, who exercises highly developed surgical skills to repair nerves and vessels barely perceptible to the human eye.
Dr. Pelham’s research involves prevention of thrombosis in microvascular surgery. New techniques and instrumentation in this area have led to improved results in microsurgical procedures. Nevertheless, thrombosis at the anastomosis site remains the most common site of failure. For this reason, most microvascular surgeons routinely use antithrombotic therapy following the procedure.
Standard heparin is the most commonly used drug for this purpose. Both unfractionated heparin and low-molecular-weight heparins exert their antithrombotic effect by binding antithrombin III and thus inhibiting thrombin and factor Xa. Clot-bound thrombin, in contrast to fluid-phase thrombin, is nevertheless resistant to inactivation by heparin. It is possible that the heparin binding site is masked while the enzyme is binding to fibrin. Because fibrin-bound thrombin mediates thrombus-associated procoagulant activity, the inability of heparin to inhibit fibrin-bound thrombin may be partly responsible for the limitations of heparin activity.
Dual-viewing microscope Dr. Pelham instructing an orthopaedic resident in microsurgical technique.
Recently, prothrombinase-associated fXa activity, like fibrin-bound thrombin, has been shown to significantly increase procoagulant activity of whole blood clots in vitro and may play a more important role than thrombin in propagating thrombus formation. When bound to the prothrombinase complex, fXa is resistant to antithrombin III–mediated anticoagulants, but not to direct inhibition by tick anticoagulant peptide (TAP). This suggests that direct inhibition of factor Xa may effectively inhibit clot formation.
Researchers have developed several synthetic inhibitors of factor Xa—potentially powerful antithrombotic drugs. Dr. Pelham’s studies seek to determine whether a new specific fXa inhibitor, C921-78, is effective in preventing thrombus formation in an arterial crush/avulsion injury model in rats. The new drug will be compared to heparin, low-molecular-weight heparin, and a saline control. Additional hematologic measurements will be taken, including coagulation parameters and bleeding time. The goal is to find an agent that will effectively inhibit thrombosis following replantation or elective microsurgery while minimally disrupting hematologic parameters so that postoperative bleeding is a minimal risk.
Making Surgery Safer
Target Condition: Clotting at the site of blood vessel repair
Traditional Approach: Administration of heparin to prevent clot formation
New Approach: Utilizing new blood clot inhibitors
Progress: Several promising compounds are being studied
Investigator Dr. Francis Pelham
An important service to the orthopaedic practitioner is provided by the microvascular specialist, who exercises highly developed surgical skills to repair nerves and vessels barely perceptible to the human eye.
Dr. Pelham’s research involves prevention of thrombosis in microvascular surgery. New techniques and instrumentation in this area have led to improved results in microsurgical procedures. Nevertheless, thrombosis at the anastomosis site remains the most common site of failure. For this reason, most microvascular surgeons routinely use antithrombotic therapy following the procedure.
Standard heparin is the most commonly used drug for this purpose. Both unfractionated heparin and low-molecular-weight heparins exert their antithrombotic effect by binding antithrombin III and thus inhibiting thrombin and factor Xa. Clot-bound thrombin, in contrast to fluid-phase thrombin, is nevertheless resistant to inactivation by heparin. It is possible that the heparin binding site is masked while the enzyme is binding to fibrin. Because fibrin-bound thrombin mediates thrombus-associated procoagulant activity, the inability of heparin to inhibit fibrin-bound thrombin may be partly responsible for the limitations of heparin activity.
Dual-viewing microscope Dr. Pelham instructing an orthopaedic resident in microsurgical technique.
Recently, prothrombinase-associated fXa activity, like fibrin-bound thrombin, has been shown to significantly increase procoagulant activity of whole blood clots in vitro and may play a more important role than thrombin in propagating thrombus formation. When bound to the prothrombinase complex, fXa is resistant to antithrombin III–mediated anticoagulants, but not to direct inhibition by tick anticoagulant peptide (TAP). This suggests that direct inhibition of factor Xa may effectively inhibit clot formation.
Researchers have developed several synthetic inhibitors of factor Xa—potentially powerful antithrombotic drugs. Dr. Pelham’s studies seek to determine whether a new specific fXa inhibitor, C921-78, is effective in preventing thrombus formation in an arterial crush/avulsion injury model in rats. The new drug will be compared to heparin, low-molecular-weight heparin, and a saline control. Additional hematologic measurements will be taken, including coagulation parameters and bleeding time. The goal is to find an agent that will effectively inhibit thrombosis following replantation or elective microsurgery while minimally disrupting hematologic parameters so that postoperative bleeding is a minimal risk.