Intimal
hyperplasia after percutaneous transluminal coronary angioplasty (PTCA) or
vascular surgical procedures remains a significant problem despite current antithrombotic
therapy. The use of the current antithrombotic drugs, namely
heparin + chronic
aspirin (ASA) +/- oral
anticoagulants, is based upon the assumptions that: i)
heparin blocks
thrombin generation and/or accelerates
thrombin inhibition by
antithrombin III (ATIII); ii)
aspirin acetylates platelet
cyclooxygenase, thereby preventing
thromboxane A2 (TxA2) synthesis; and iii) oral
anticoagulants reduce the availability of
vitamin K-dependent procoagulants, thereby reducing the risk of
thrombus formation. Albeit beneficial, this approach has a number of shortcomings and limitations: i) when
thrombin binds to an injured vessel wall, it becomes resistant to inhibition by
heparin/ATIII; thus, surface-bound
thrombin remains active, stimulating further
thrombus formation, smooth muscle cell proliferation and subsequent
hyperplasia; ii) while TxA2 inhibition reduces platelet reactivity, platelets are able to respond to multiple stimuli generated at the time of, or after, vessel wall injury; and iii)
heparin,
aspirin and the oral
anticoagulants all render the patient hemostatically defective and at risk of
bleeding. Recent studies suggest that alternate therapeutic approaches can inhibit thrombogenesis more effectively at the time of injury, thereby not only inhibiting
hyperplasia more effectively than the currently used drugs, but also reducing (or eliminating) the need for long-term
therapy. For example, we suggest that the
heparin cofactor II (HCII) catalysts,
dermatan sulfate and
Intimatan, inhibit surface-bound
thrombin more effectively than
heparin/ATIII, thereby inhibiting intimal
hyperplasia effectively. Their effects are achieved when the
drug is given only at the time of injury; i.e. with no further antithrombotic
therapy. Other studies indicate that injured vessel wall thrombogenicity can be reduced by pretreatment with
Persantine (
dipyridamole) or with certain
fatty acid supplements which either increase vessel wall cAMP and/or 13HODE synthesis. These increases are associated with decreased vessel wall thrombogenicity, which, in turn, is associated with decreased intimal
hyperplasia. Such results suggest that vessel wall repair is achieved more effectively by targeting antithrombotic drugs directly at the vessel wall thrombogenicity per se rather than indirectly by altering the circulating blood cells and systemic
coagulant system.