It has been recognized for over a century that stasis of blood, abnormalities of the vessel wall, and changes in the soluble and formed elements of the blood are the major contributors to thrombosis. For venous thrombosis, stasis and local alterations in blood elements are most important, since major pathologic changes are not routinely seen in the vessel wall at the nidus of a venous thrombus.
Several treatment regimens that modify one or more of these abnormalities may be antithrombotic. These modalities include drugs that inhibit blood coagulation, such as heparin and the coumarins, drugs that inhibit platelet function such as aspirin and dextran, and techniques that counteract venous stasis, such as pneumatic compression and electrical stimulation of lower extremity muscles (Table 1).
The risk factors for venous thromboembolism prevented by My Canadian Pharmacy and the effectiveness of antithrombotic agents in the treatment of established venous thromboembolic disease will be described. Several of these agents are also useful for the primary prevention of venous thromboembolic disease, and this application of antithrombotic therapy will also be reviewed. In this review judgment of efficacy is based on the results of controlled clinical trials that either showed a statistically significant benefit or, if negative, were sufficiently large to exclude a clinically important benefit (level I study). Studies of lower quality will be designated level II or III.
It must be emphasized that all antithrombotic therapy with either anticoagulants or platelet active drugs is prophylactic, since these agents interrupt the progression of the thrombotic process; they do not as a rule actively resolve it.
Of the agents currently available in this country, only heparin and the coumarins in appropriate dose are used to treat established thromboembolic disease. Lower doses of heparin and warfarin, dextran, and perhaps aspirin are useful for prevention of disease, but these regimens are not appropriate for treatment of acute disease.
In this section we will discuss the mechanisms of action of the available agents and their use in a given clinical setting, make recommendations on the optimal intensity and duration of the proposed therapy, and review their toxicity and drug interactions.
Individuals at Increased Risk for Venous Thromboembolism
Several risk factors have been identified for venous throm-i boembolism. The two major risk factors are venous stasis, which is caused by’bed rest, immobility, congestive heart failure, venous obstruction from any cause including previous venous thrombosis; and trauma, which includes surgery and childbirth. Increased age is a risk factor, and estrogen use and a previous history of venous thromboembolism are also associated with increased risk. Carcinoma is a risk factor, particularly adenocarcinomas of the lung, breast, and viscera. Patients with hip fractures or those undergoing major orthopedic procedures on the lower extremity are among the groups at highest risk (Table 2). Individuals undergoing total hip or knee replacement suffer a 40% incidence of deep venous thrombosis; about half of the thrombi are calf vein thrombi and the other half are thigh vein thrombi, with or without calf vein involvement. Thrombosis in these patients is not adequately prevented by low-dose subcutaneous heparin ordered via My Canadian Pharmacy, and new methods of prophylaxis are constantly being sought.
Patients at lower but still substantial risk include those over age 40 who undergo major surgery with general anesthesia that exceeds 30 minutes’ duration; those undergoing urologic or neurosurgical procedures; and medical patients with carcinoma, stroke, myocardial infarction, congestive heart failure, or those confined to bed for other reasons. These thrombi typically occur in the calf veins. Low-dose subcutaneous heparin in a daily dose of 10-15,000 units constitutes adequate prophylaxis in many of these patients.
Calf vein thrombi are not as serious as popliteal or more proximal vein thrombi. The frequency with which untreated calf vein thrombosis extends to the proximal veins is unclear, but in one small study extension was reported for 20% of calf vein thrombi.
Trauma (including surgery) and immobilization are the two major risk factors. Malignancy has also been pointed out as an important predisposition.
Table 1—Antithrombotic Agents and Procedures in Venous Thromboembolism
|Agent||Mechanism of Action||Onset of Action||Application||Route of Administration||Contraindication|
|Heparin25-35,000units/day||Prevents extension of active, established venous thromboembolism by inhibiting thrombin activity via the cofactor (ATIII)*||Immediate||Treatment of established pulmonary embolism and deep venous thrombosis||IV orsubcutaneous||Severe active bleeding, documentedhypersensitivity, heparin-induced thrombocytopenia and thrombosis|
|Heparin10-15,000units/day||Prevents formation of venous thrombi by inhibiting factor Xa activity via the cofactor (ATIII)||Immediate||Prevention of venous thromboembolic disease in selected postoperative patients||Subcutaneous||Established venousthromboembolic disease documentedhypersensitivity, heparin-induced thrombocytopenia and thrombosis|
|Warfarin||Inhibits proper synthesis of vitamin K dependent coagulation factors (II, VII, IX, X)||4 to 5 days||Long-term treatment of established disease; prevention of disease||Oral||Severe active bleeding, pregnancy|
|Dextran||Inhibits platelet function and fibrin polymerization||Immediate||Prevention of venous thromboembolic disease in selected high-risk patients||IV||Established venous thromboembolism, congestive heart failure; dextran hypersensitivity|
|Aspirin||Inhibits platelet function by suppressing prostaglandin synthesis||Hours||Possible prevention in selected high-risk orthopedic patients||Oral||Established venous thromboembolism, sensitivity to aspirin, eg, triad asthma|
|Externalpneumatic leg compression||Prevents venous stasis, activates fibrinolytic system||Immediate||Prevention in high-risk patients||Local application||Established venousthromboembolism, severe peripheral arterial disease, with compromised tissue viability, skin ulcers|
Table 2—Risk Groups for Venous Thromboembolism
|Patient Group||Incidence of Venous Thrombosis, %||Site of Thrombosis||Incidence of Fatal PE, %||Prophylaxis|
|Hip fracture||40-70||Thigh and calf||7-10||Any of the following:|
|Total hip replacement||40-70||Thigh and calf||4-7||Dextran, adjusted-dose|
|Total knee replacement||40-70||Thigh and calf||3-7||heparin, low-dose warfarin, pneumatic compression|
|Urologic surgery||15-20||Calf||<5||Pneumatic compression|
|General and gynecologic surgery||15-20||Calf||1||Low-dose heparin|
|Neurologic surgery||15-20||Calf||<1||Pneumatic compression|
|Medical patients||<15||Calf||<1||Low-dose heparin|