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Statement of Problem
Deep venous thrombosis (DVT) remains a serious health problem, with over 250,000 patients affected and at least 200,000 yearly diagnosed with pulmonary embolism (PE), although these figures may be conservative, and treatment costs in the billions of dollars. Chronic venous insufficiency (CVI) affects 400,000 to 500,000 patients with skin ulceration and 6 to 7 million patients with stasis pigmentation and stasis dermatitis. The prevalence of leg ulceration is 5/1000 among persons greater than 20 years old, and more than one-half of these are the result of a previous DVT. Approximately 1% of adults and 3% to 4% of those greater than 65 years old once had or now have an ulcer from a venous etiology. This review will begin with the currently accepted therapies for the initial treatment (prior to long-term oral anticoagulation) of venous thromboembolism.
Heparin
Standard unfractionated heparin is a complex mixture of glycosaminoglycans that contain a vital pentasaccharide, which activates antithrombin III resulting in enhanced inactivation of thrombin and factor Xa among other factors of the coagulation system. Successful anticoagulation requires heparin lengths generally greater than 18 saccharide units to bind both antithrombin III and thrombin and inhibit thrombin. Although effective in the treatment of venous thromboembolic disease preventing fatal PE (however venous thrombosis extension/recurrence rates of 20% to 30% are common), there are limitations to standard heparin including the need for parenteral administration, intravenous infusion in most cases, and need for frequent anticoagulation monitoring. Additionally, the administration of drug may be complicated by bleeding, thrombocytopenia, and over the long-term, alopecia and osteoporosis.
Low-Molecular-Weight Heparin
Low-molecular-weight heparin (LMWH) resulted from the recognition that only the short heparin chains are needed to increase the antifactor Xa activity of antithrombin III. Due to less antithrombin activity and less antiplatelet activity, these compounds cause less severe bleeding. They also have a more predictable bioavailability due to their lack of binding to plasma proteins and endothelial cells. Originally introduced for DVT prophylaxis, they now have been shown in worldwide studies to be at least equivalent to, if not better than, standard heparin for the treatment of DVT and even PE in regards to recurrent thrombembolic events, bleeding, and mortality. However, they still require frequent (qd to bid) parenteral administration and they still can lead to thrombocytopenia, although they can be given subcutaneously (rather than by continuous intravenous administration) and do not require the same frequent coagulation monitoring. The main problem with LMWH at the present time is the poor insurance coverage for this drug when prescribed in the outpatient setting, the setting which is most appropriate for its use.
Oral Heparins
Oral heparins are being developed to allow for absorption through the gastrointestinal tract. One of the approaches has been to complex either heparin or LMWH to a carrier protein to allow for the drug to pass through the intestinal mucosal barrier. Examples of this include the compound called SNAC (for standard heparin) and SNAD (for LMWH), and deoxycholic acid (for both). These drugs would most likely be targeted to replace long-term oral anticoagulants such as coumadin.
Thrombin Inhibitors
Direct thrombin inhibitors have shown promise as anticoagulants, and certain compounds have been approved for use in specific clinical situations. Recombinant hirudin (desirudin, lepirudin) and its semi synthetic analogues (bivalirudin, argatroban) act to directly inhibit thrombin, both free and bound to fibrin, without the need for a cofactor such as antithrombin III. Lepirudin and argatroban have been approved for use in heparin induced thrombocytopenia, where they have reduced the incidence of recurrent thromboembolic complications. Desirudin and hirudin have been evaluated in the prophylaxis and treatment of DVT. However, direct thrombin inhibitors have a narrow therapeutic window, making them difficult to use. The newest development is an oral direct antithrombin, H 376/95, which is converted to the direct thrombin inhibitor melagatran. This compound has shown promise in the treatment of DVT.
Defibrination
Another approach to anticoagulation is the use of an agent that produces systemic defibrination, called ancrod. It acts on circulating fibrinogen, cleaving fibrinopeptide A but not fibrinopeptide B. Additionally, factor XIII is not activated, making a clot that is more easily digested by plasmin. Local production of tissue plasminogen activator, increased by the resulting fibrin monomers, in combination with depleted fibrinogen stores, also results in rapid, effective systemic anticoagulation. Ancrod therapy is monitored by fibrinogen levels. In limited studies, it has been used in the prophylaxis and treatment of DVT.
Antiplatelet and Others
The use of antiplatelet therapies has undergone wide study in the arterial circulation, but virtually no studies (other than for DVT prophylaxis) exist regarding antiplatelet agents and venous thrombosis. Other agents which are being investigated for DVT include active site-inactivated factor VIIa inhibitors, tissue factor pathway inhibitor, and activated protein C.
Pentasaccharide
One of the more exciting areas under investigation for the prophylaxis and treatment of DVT is synthetic pentasaccharide. This is a compound that consists of five saccharide units positioned to bind strongly and exclusively to antithrombin. It has been shown to be more effective than LMWH in DVT prophylaxis in high-risk orthopedic procedures, and studies regarding its use in DVT treatment are underway.
Coming from the Bench top - Selectin Inhibition
In mice, rat, primate, and clinical studies, after venous thrombus formation, an acute to chronic inflammatory response occurs in the vein wall and thrombus, leading to thrombus amplification, thrombus organization, and vein wall and valvular damage. A balance between pro-inflammatory and anti-inflammatory cytokines/chemokines determines the ultimate vein response. The earliest up-regulated glycoprotein on endothelial cells and platelets, P-selectin, plays a central role in thrombogenesis. In mouse venous thrombosis, P-selectin is elevated before E-selectin, with appropriate mRNA elevations. Gene targeted mice for E-selectin and combined P-selectin/E-selectin demonstrate less thrombus, while P-selectin/E-selectin and P-selectin gene targeted mice show less inflammation. In primate venous thrombosis, P-selectin inhibition given prophylactically decreases thrombosis. Selectin inhibition also treats established venous thrombosis as effectively as LMWH, without anticoagulation. We hypothesize that selectins, expressed after a thrombogenic stimulus, facilitate leukocyte-endothelial cell, leukocyte-leukocyte, and leukocyte-platelet interactions, stimulating fibrin formation. Procoagulant microparticles are recruited to thrombi, where they amplify coagulation via tissue factor. Agents that interfere with selectins such as antibodies to P-selectin or a receptor antagonist to the P-selectin receptor PSGL-1 (termed rPSGL-Ig) should interfere with thrombus amplification, allowing for an antithrombotic effect without anticoagulant-induced bleeding. Interference with thrombus amplification should also facilitate the natural fibrinolytic system to lyse whatever thrombus that does form, decreasing overall thrombus burden and preserving vein wall and valvular integrity. In summary, selectin inhibition may provide an exciting new modality to prevent propagation of thrombus and diminish the long term sequelae of venous thrombosis
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