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A rationale for targeting antithrombotic therapy at the vessel wall: improved antithrombotic effect and decreased
1Department of Pathology and Molecular Medicine, McMaster University, Ontario, Canada. mbuchanan@fhs.mcmaster.ca
Insights
New antithrombotic therapies targeting vessel wall thrombogenicity show promise in preventing intimal hyperplasia after vascular procedures. These approaches may offer more effective treatment with reduced long-term therapy needs.
Area of Science:
- Cardiovascular Research
- Thrombosis and Hemostasis
- Vascular Biology
Background:
- Intimal hyperplasia remains a significant issue post-percutaneous transluminal coronary angioplasty (PTCA) and vascular surgery, despite current antithrombotic treatments like heparin, aspirin (ASA), and oral anticoagulants.
- Existing therapies have limitations: thrombin bound to injured vessel walls resists heparin inhibition, platelets react to multiple stimuli, and treatments increase bleeding risk.
- Current antithrombotic strategies indirectly target circulating factors, offering incomplete protection against vessel wall-mediated thrombogenesis and hyperplasia.
Purpose of the Study:
- To explore novel therapeutic approaches for inhibiting thrombogenesis and intimal hyperplasia more effectively after vascular injury.
- To investigate treatments that target vessel wall thrombogenicity directly, potentially reducing or eliminating the need for long-term antithrombotic therapy.
- To compare the efficacy of targeting surface-bound thrombin and vessel wall reactivity versus traditional systemic anticoagulation.
Main Methods:
- Review of recent studies on alternative antithrombotic strategies.
- Evaluation of heparin cofactor II (HCII) catalysts (dermatan sulfate, Intimatan) for inhibiting surface-bound thrombin.
- Analysis of studies involving vessel wall pretreatment with dipyridamole (Persantine) or fatty acid supplements to modulate thrombogenicity.
Main Results:
- HCII catalysts demonstrated effective inhibition of surface-bound thrombin, leading to reduced intimal hyperplasia with single-dose administration at the time of injury.
- Pretreatment with dipyridamole or specific fatty acids increased vessel wall cyclic adenosine monophosphate (cAMP) and/or 13-hydroxyoctadecadienoic acid (13-HODE) synthesis.
- Increased cAMP and 13-HODE synthesis correlated with decreased vessel wall thrombogenicity and subsequent reduction in intimal hyperplasia.
Conclusions:
- Targeting vessel wall thrombogenicity directly offers a more effective strategy for preventing intimal hyperplasia compared to indirect systemic anticoagulation.
- Heparin cofactor II (HCII) catalysts show potential for potent inhibition of intimal hyperplasia with on-demand, single-dose therapy.
- Modulating vessel wall reactivity through agents like dipyridamole or fatty acids presents a promising alternative for managing post-procedural vascular complications.
Abstract:
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.