This study will test the effectiveness of low-dose recombinant tissue plasminogen activator
(rtPA, or alteplase) in dissolving blood clots in deep leg veins. rtPA is given to patients
with heart attacks to dissolve blood clots in blocked coronary arteries. Blood clots that
develop in the deep leg veins can cause pain and swelling and may break loose and lodge in
the lungs. Current Routine treatments use anticoagulants (blood thinners) such as heparin,
or rtPA to dissolve the clots to stop the clots from enlarging. 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 effectively dissolve clots with fewer bleeding complications
than the current previous higher-dose regimen.
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 3 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, and Coumadin, another blood thinner, taken by mouth. Patients
continue taking Coumadin for 6 months.
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
To evaluate the impact of treatment on the function of the leg, patients are evaluated in
the Rehabilitation Medicine Department before receiving rtPA and again at the end of the
hospitalization. Patients are also fitted for a compression stocking for the leg, which
should be worn to reduce the chance of swelling.
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
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.
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
Atrial fibrillation, unless a cardiac echocardiogram excludes the presence of intracardiac
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.