Low-Dose Alteplase to Treat Blood Clots in Deep Leg Veins
Condition: Acute Deep Venous Thrombosis of the Lower Extremity
MeSH terms: Thrombosis; Venous Thrombosis
Intervention: Alteplase (Activase, Genentech)
Intervention description: Dose of Alteplase will not exceed 10 mg/d/leg and is delivered in a concentration of 100ug/mL. The actual dose delivered is based upon the length of the thrombosed vein and 1 mL is injected directly into each centimeter of a thrombosed vein in a lower extremity. The treatment will be repeated up to 4 times over a 4 day period.
Intervention MeSH terms: Tissue Plasminogen Activator
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: r-tPA; Thrombolysis; Clot; Anticoagulation; Fibrinolysis; Deep Vein Thrombosis; DVT

Summary:

      This study will test the effectiveness of low-dose recombinant tissue plasminogen activator
      (rtPA, or alteplase) in dissolving blood clots in deep leg veins. Alteplase is used to clear
      blood clots in coronary arteries in patients having heart attacks. Blood clots can develop in
      the deep leg veins causing pain and swelling and may break loose and lodge in the lungs.
      Current routine treatments use anticoagulants such as heparin stop the clots from enlarging
      and prevent clots from moving to the lung but do not reliably dissolve clots in the leg.In an
      earlier study we showed that rtPA could be used to actually dissolve the clots. This study
      will determine whether lower doses of rtPA can dissolve clots with fewer bleeding
      complications than the current higher-dose regimens.

      Patients 18 years of age and older who have blood clots in a deep vein of the pelvis or leg
      may be eligible for this study if they have had symptoms for 14 days or less and if they have
      never had clots in their deep veins before.

      Participants are admitted to hospital for up to 5 days. On the first treatment day, the
      patient has a venogram to show the location of the clots. The radiologist injects an x-ray
      contrast material into a small vein in the foot and watches the dye by x-ray as it moves up
      the leg, revealing the clot(s). A catheter (plastic tube) is then inserted into a vein either
      behind the knee, in the groin, or in the neck, and advanced until it reaches the clots. When
      the catheter is in place, rtPA is injected while the radiologist watches the vein under the
      x-ray image. The amount of rtPa needed will depends on the size of the clot. Up to five
      venograms may be done if the clot requires the maximum four rtPA treatments allowed in this
      study. During the treatments, patients receive standard doses of heparin, given continuously
      by vein, After completion of treatments, anticoagulation is continued through use of a low
      molecular weight heparin (usually enoxaparin) given by subcutaneous injection as a transition
      medication during conversion to anticoagulation with warfarin ( also known as coumadin),
      another blood thinner, taken by mouth. Patients continue taking warfarin for 6 months.

      During thrombolytic therapy, blood samples are drawn shortly before the first dose of rtPA
      and at five time points afterward to measure the rtPA in the circulation and other factors
      that indicate whether the rtPA is affecting clotting ability. Blood also is drawn at least
      once a day to monitor heparin levels.

      To evaluate the impact of treatment on the function of the leg, patients return to the
      Rehabilitation Medicine Department and Radiology department at about 6 weeks (4 to 8 week )
      and 6 months for clinical and imaging evaluation of impact of therapy on venous function.

      The objectives are to determine how well this treatment will restore venous function and
      whether this can be done safely- without causing bleeding complications, which have been the
      main risks of previous thrombolytic treatments.
    

Eligibility criteria:

        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 (PTT) greater than 15 s, an
             activated partial thromboplastin time (aPTT) greater than 35 s, or a platelet count
             less than 100,000/microliter 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 noncompressible
             vessel, organ biopsy, or cardiopulmonary resuscitation.

          -  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.