• Efficacy: ability to restore venous function in lower extremities affected by deep vein thrombosis. [ Time Frame: 5 days ] [ Designated as safety issue: Yes ]
  

• Safety [ Time Frame: 5 days ] [ Designated as safety issue: Yes ]
  

Drug: Alteplase (Activase, Genentech)
Plasminogen Activator (fibrinolytic enzyme)

Deep venous thrombosis (DVT) of the lower extremities is routinely treated with anticoagulants, which typically yield a satisfactory result, at least in the short term. However, DVT often causes permanent vein damage that leads to late complications. There is evidence that this may be prevented, and therefore long-term sequellae avoided, if the thrombi are dissolved quickly with thrombolytic agents. In a previous protocol we developed a method using intra-clot injections of alteplase (recombinant tissue plasminogen activator, rtPA) for the treatment of lower extremity DVT. Although the treatment was usually successful and complications were uncommon, we think the regimen can be made safer and perhaps even more effective by using a substantially lower dose of alteplase. The current protocol is a pilot study to test this hypothesis. Up to 25 patients with first-time DVT symptomatic for less than or equal to 14 days will be accepted from referring physicians both within and outside the NIH. They will be treated with less than or equal to 10 mg alteplase per day for up to four days. The protocol is designed so that if the low-dose regimen is unsuccessful, the patient will subsequently receive the higher-dose regimen that has previously been shown to be effective. The patients will be anticoagulated for approximately 6 months and re-evaluated after approximately 6 weeks and approximately 6 months with venography and/or duplex sonography.

• INCLUSION CRITERIA

Only adult patients (18 years old or older) are included.

Patients must have thrombosis documented by ultrasound or venography to involve the deep veins of the pelvis and/or a lower extremity proximal to the calf veins, i.e., the popliteal vein or above.

The thrombosis must be the patient's first DVT.

The thrombosis must have been symptomatic for no more than 14 days.

Patients must be able to give informed consent and be able to follow the prescribed anticoagulation regimen.

Patients on concurrent NIH protocols will be eligible as well as patients from the community and the rest of the U.S. who are not already on NIH protocols.

EXCLUSION CRITERIA

Pregnant patients are not eligible, although postpartum mothers over 10 days from delivery are eligible if they refrain from breast feeding their infants for 24 hours after each study with x-ray contrast material.

Serum creatinine greater than than 2 mg/dL.

Any current bleeding diathesis not attributable to heparin or warfarin. Fibrinogen less than 150 mg/dL. Any patient with a prothrombin time greater than 15 s, an aPTT greater than 35 s, or a platelet count less than 100,000/microL must be evaluated by the Hematology Service for a coagulopathy before being included.

Within the previous 10 days: major surgery or trauma, puncture of a noncompresssible vessel, organ biopsy, or cardiopulmonary resusitation.

Within the previous 2 months: cerebrovascular infarction or hemorrhage, or intracranial or intraspinal surgery or trauma.

Within the previous 6 months: major internal bleeding.

Active intracranial disease (aneurysm, vascular malformation, neoplasm).

Life expectancy less than 6 months.

Patients with hemoglobin concentration less than 9g/dL will not participate in the pharmacokinetic portion of the protocol.

Uncontrolled systolic blood pressure greater than 180 mm Hg or diastolic greater than 100 mm Hg.

Atrial fibrillation, unless a cardiac echocardiogram excludes the presence of intracardiac thrombus.

Known right-to-left intracardiac shunt.

Pericarditis, infective endocarditis.

History of heparin-induced thrombocytopenia within 6 months or the presence of persistent anti-heparin antibodies by ELISA.

History of anaphylactic reactions to x-ray contrast media.

Known retinopathy unless cleared by an ophthalmologist at NIH.

Evidence of uncontrolled congestive heart failure or a history of diabetes mellitus.