Use of Alteplase (tPA) for Thrombolytic Therapy

Mechanism of Action

• Local fibrinolysis by binding to fibrin, converts entrapped plasminogen to plasmin

Half-Life

• ~5 minutes

Metabolism

• Primarily liver

Pharmacokinetics – Time to peak

• Immediate

Dosing – Adult

• Please see additional information

Dosing – Pediatric

• Bolus: none
• Maintenance: 0.5 mg/kg/hr continuous infusion for 6 hours. Administer concurrently with low-dose UFH at 10 IU/kg/hr to prevent further thrombus formation*

Monitoring

• PT
• APTT

* If previously on UFH reduce infusion rate 30 min prior to rt-PA. Increase UFH rate to full dose 30 min after completion of a 6-hr infusion of rt-PA.

Dosing
Numerous dosing strategies for alteplase (tPA) are used for thrombolytic therapy in pediatrics and there is currently no consensus as to which approach is optimal. Higher doses may restore flow more rapidly, but appear to have a higher risk of bleeding. The regimen used may depend upon the type of thrombotic event, as discussed below.

SYSTEMIC THROMBOLYSIS:
Concurrent Heparin Therapy:
Initiate heparin at 10-15 u/kg/h (no bolus); may need 15-20 u/kg/h for infants

Low Dose Alteplase (tPA) Regimen
Should be considered for patients with non life-threatening venous thrombotic events.
Initial Dose: 0.03-0.06 mg/kg/hr for venous thrombosis (infants less than 3 months likely to require 0.06 mg/kg/hr). Max dose for low dose alteplase (tPA): 2 mg/hr, with max total dose of 100 mg.
Duration: Dose may be continued for a relatively prolonged duration (12-48 hours). Ongoing monitoring of hematologic parameters (see below Monitoring) and thrombus assessment are essential.

High Dose Alteplase (tPA) Regimen
Should be considered for patients with arterial and/or more critical thrombotic events. For most neonates and infants, low dose alteplase is recommended.
Initial Dose: 0.1-0.6 mg/kg/hr with max total dose of 100 mg infused over 6 hours.
Duration: Duration will depend upon the dose. Patients receiving doses of 0.5-0.6 mg/kg/hr should be assessed at 6 hours. At 6 hours, hematologic parameters and thrombus assessment should be performed (see below Monitoring). Re-image at 6 hours to assess need for ongoing therapy. If persistent clot still present, hematologic parameters are within acceptable range (see contraindications for thrombolysis) and the patient is stable, a second 6-hour infusion can be administered in 6-12 hours. Patients at the lower end of this dose range may tolerate longer infusions.

Pulmonary Embolism Protocol (see Pulmonary Embolism Protocol)
Dose/Duration: 

• High dose:  0.5 mg/kg/hour; duration may range from 2-6 hours [or longer; but shorter favored over longer] for a total of 3 mg/kg with maximum dose of 100 mg.
• High dose (PE with arrest/peri-arrest): 0.5 mg/kg bolus (max 2 mg/dose) over 5 min. May repeat after 15 min.
• Low dose:  0.1-0.3 mg/kg/hour; duration may range from 2-6 hours [or longer; but shorter favored over longer] for a total of 0.6-1.8 mg/kg with maximum dose of 50 mg.

Periprocedural anticoagulation management 

• Hold alteplase (tPA)/heparin a minimum of 6 hours prior to surgical procedure or lumbar puncture.
• Restart after the procedure as soon as adequate hemostasis has been established and once cleared by the surgeon or interventionalist.

Indication
Indications for thrombolysis in the treatment of pediatric TE are not well established, primarily due to lack of well-designed clinical studies. The benefit of rapid clot resolution must be weighed against the risk of major bleeding, which is greater than with anticoagulation alone. As a result, indications for thrombolytic therapy in children should be restricted to situations in which the benefit of rapid thrombus resolution is thought to outweigh the risk of major hemorrhage:

1. Life, limb or organ threatening thrombosis
   • Arterial thrombosis causing tissue ischemia, venous thrombosis with compartment syndrome
   • Superior vena cava syndrome due to thrombosis
   • Massive PE with cardiovascular instability
   • Bilateral renal vein thrombosis
   • Cerebral sinovenous thrombosis with progressive neurologic
   • decline
   • Large atrial thrombi
2. Extensive obstructive proximal iliofemoral vein or inferior vena cava
3. thrombosis
   • Anatomic compressive syndromes
     • May-Thurner Syndrome
     • Paget-Schroetter Syndrome
4. Thrombotic events in which the long-term persistence of thrombus would have a significant negative effect (e.g., prosthetic heart valve thrombosis, congenital heart disease with thrombotic shunt obstruction)

Contraindications to Systemic Thrombolytic Therapy

• Major surgery within 7-14 days (including puncture of noncompressible vessel, lumbar puncture, organ biopsy, cardiopulmonary resuscitation)
• Active bleeding (if female is menstruating, consult with GYN and cessation of menstrual bleeding recommended prior to tPA)
• CNS surgery, trauma, ischemia*, hemorrhage within 30 days, including intraspinal surgery or trauma
• Inability to maintain platelet count > 100,000/mm3
• Inability to maintain fibrinogen >100 mg/dl
• Severe Coagulopathy
• Uncontrolled hypertension > 95th percentile for age and gender
• Active intracranial disease (aneurysm, vascular malformation, neoplasm)
• Sepsis, pericarditis, infective endocarditis
• Uncontrolled seizure during preceding 48 hours
• Pregnancy
• Extreme prematurity
• Known bleeding disorder / tendency
• Hypersensitivity to alteplase
• Recent warfarin use with INR >/= 1.6 at time of thrombolysis (discuss reversal with hematology)
• Additional contraindications for use of alteplase for acute ischemic stroke are listed in the Stroke Protocol.

*With the possible exception of acute ischemic stroke per IHTC/PMCH stroke team

** Seizures are not necessarily a contraindication where they are judged to be symptomatic of acute ischemic stroke, per IHTC/PMCH stroke team.

Relative Contraindications to Thrombolytic Therapy

• Major internal bleeding within the previous 6 months
• Atrial fibrillation, unless a cardiac echocardiogram excludes presence of intracardiac thrombus
• Known right-to-left intracardiac shunt
• History of HIT within 6 months or the presence of persistent anti-heparin antibodies by ELISA. Anticoagulation with bivalirudin or argatroban should be used in place of heparin.
• Serum creatinine > 2 mg/dL.

These contraindications are not absolute or evidence based, and in every individual clinical situation, the relative risks of thrombolytic therapy must be weighed against potential benefits.

USE

Initiating Therapy

• Prior to initiation of therapy, but no longer than 48 hours before, or, upon initiation of alteplase (tPA) infusion, the following labs should be checked: CBC (thrombocytopenia is a relative contraindication to thrombolytic therapy and should be corrected to ≥ 100,000/mL before use), coagulation profile (PT, PTT, fibrinogen activity, d-dimer), hepatic function panel, creatinine, type & screen, urine pregnancy if applicable.
• A head ultrasound in all infants < 1 month old or CT brain for older children whose neurologic status is difficult to assess (to exclude intracranial hemorrhage). A head ultrasound/imaging is also suggested for other high risk patients (i.e., patients < 1 year old, trauma patients, infants with recent history of cardiac surgery) prior to thrombolytic therapy.

Route of Administration 

• Thrombolytic drugs may be administered systemically (systemic thrombolysis) or directly into the thrombus via a catheter that has usually been placed specifically for that purpose (catheter-directed thrombolysis). This decision is generally made on a case-by-case basis. In older patients, site-directed thrombolysis may allow lower doses of alteplase (tPA) because the catheter is near the site of occlusion, and allows for easy reimaging of the site. Consider systemic thrombolysis if site-directed is technically difficult or not easily obtainable.
  • Patients must have a dedicated line for alteplase (tPA) infusions.
  • The infusion must NOT be stopped or interrupted for other medications.

Stroke:
See Stroke Protocol.

CATHETER DIRECTED THROMBOLYSIS (For use by IR, Vascular, or Cardiology)
As per IR/Vascular at PMCH.

• Absolute contraindications to CDT:
  • 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.
  • Any current bleeding diathesis not attributable to heparin or warfarin.
  • Fibrinogen < 100 mg/dL
  • Plt count < 100k unless platelet count can be raised to  >/=100k by platelet transfusion or other therapy as per IHTC recommendations prior to undergoing thrombolysis
  • Uncontrolled systolic BP > 180 mgHg or DBP > 100 mmHg (for children: SBP and DBP >95th percentile for age and gender)
  • History of anaphylactic reactions to contrast media
  • Relative contraindications to CDT:
  • Serum creatinine > 2 mg/dL.
  • 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).
  • Atrial fibrillation, unless a cardiac echocardiogram excludes the presence of intracardiac thrombus.
  • Known right-to-left intracardiac shunt.
  • Known pericarditis, infective endocarditis.
  • History of heparin-induced thrombocytopenia within 6 months or the presence of persistent anti-heparin antibodies by ELISA. Anticoagulation with argatroban should be used in place of heparin.

If female is menstruating, consult with GYN and cessation of menstrual bleeding recommended prior to tPA.

These contraindications are not absolute or evidence based, and in every individual clinical situation, the relative risks of thrombolytic therapy must be weighed against potential benefits.

USE OF CONCOMITANT ANTICOAGULATION
The use of UFH during both systemic and CDT may be helpful in preventing ongoing thrombus formation but will increase the risk of bleeding. This decision should be made on an individual basis.

• Systemic thrombolysis and/or critically ill patients at high risk for bleeding: heparin at 10-15 u/kg/h (can target anti-Xa level of 0.1-0.3 if high risk of bleeding). If previously on full dose UFH, reduce infusion rate 30 min prior to tPA.
• Catheter-directed thrombolysis: typically 10-15 u/kg/hr up to full dose UFH rate (if cleared by IR to give UFH bolus, ok to give bolus for CDT)
• In cases where alteplase is used to treat acute ischemic stroke, other antithrombotic treatments, such as heparin, warfarin, aspirin, are held for at least 24 hours.

Monitoring Therapy During Systemic Thrombolysis

• An elevated d-dimer and drop in fibrinogen is indicate of a lytic state.
• PTT, fibrinogen q6h and at end of tPA infusion
• D-dimer q12h and at end of tPA infusion
• CBC q6h, unless sudden drop in blood pressure or extensive active bleeding
• Goals
  • Fibrinogen 100-200 (expect to decrease by 20-50% with adequate therapy)
  • D-dimer elevated
  • PTT 40-60 sec
  • (ACT 160-200 sec)
  • Hgb stable
  • Plt count >100k (transfuse to maintain plt count)
• Titrate tPA dose to fibrinogen/d-dimer
  • If fibrinogen >200, increase tPA
  • If d-dimer low, increase tPA
  • If fibrinogen <100, give FFP 10 cc/kg if it has been more than 24 hours on tPA (as this replaces plasmin[ogen] = substrate for tPA) or cryoprecipitate 1 unit per 5 kg if less than 24 hours on tPA or insufficient increase in fibrinogen with FFP
  • If fibrinogen persistently <100, decrease tPA dose by 25%
• Expect oozing from line/puncture sites; this is an indication that thrombolysis is occurring and NOT an indication to stop the tPa infusion. For minor bleeding, hold pressure, can apply topical thrombin for mucocutaneous bleeding/bleeding venipuncture sites.
• Don’t forget to re-assess and re-image at 6 hours (higher dose) or 12-24 hours (low dose) intervals to assess need for ongoing therapy.
• Vitals and O2 sat every 1 hours (systemic) or every 4 hours (catheter-directed)
• Neurochecks sat every 1 hours (systemic) or every 4 hours (catheter-directed)
• Signs/ symptoms of bleeding & dressing assessment (if applicable) every 1 hour

Complications of Therapy

• For major bleeding and/or if acute > 2 gm drop in Hgb in a 12-24 h period or physical exam or symptoms consistent with major bleeding (intracranial, retroperitoneal, massive gastrointestinal):
  • Stop tPA infusion/heparin
  • Transfuse with pRBCs
  • Image to evaluate for bleeding and to re-evaluate need for tPA therapy
  • Consider FFP/cryo (cryo if concern for major bleeding)/protamine
  • Can give Amicar for tPA reversal (discuss with IHTC)
• If Hgb drops 2 gm over a couple of days, do not stop tPA. This can be expected from the minor oozing. Transfuse with pRBCs and re-evaluate.

End of Therapy

• Indications to discontinue therapy
  • Clot resolution
  • Major hemorrhage
  • Lack of clot resolution after several doses (determined with the help of IHTC)
• Begin therapeutic doses of heparin or LMWH after tPA is discontinued (30 min. after completion of tPA).