Mechanism of Action

• Argatroban is a synthetic direct thrombin inhibitor (DTI) that reversibly binds to the thrombin active site, thereby blocking thrombin-mediated propagation of the coagulation cascade

Pharmacokinetics

• Half-Life: ~45 min.
• Metabolism: Mainly liver
• Onset of action: Immediate-30 min.
• Steady state reached: 1 to 3 hours
• Protein/albumin binding?: Yes

Dosing – Pediatric

• Heparin-induced thrombocytopenia is the primary FDA-approved indication for argatroban

Initiating Therapy

• Prior to initiation of therapy, but no longer than 48 hours before, the following laboratory values are checked: CBC, coagulation panel (PT, PTT, fibrinogen activity), creatine, hepatic function panel, pregnancy test for females if applicable
• Argatroban should be ordered using dosing weight regardless of BMI. Dosing has been studied in patients up to 140 kg. If weight > 140kg, there is no contraindication; however, closer monitoring and clinical judgment is recommended.
• A brain ultrasound is suggested for patients less than 1 year old. If possible to be completed, a brain ultrasound is STRONGLY recommended for neonates less than 44 weeks corrected gestational age.
• When possible, patients should have a dedicated IV line for argatroban. The argatroban infusion must not be stopped or interrupted for other medications except in cases of emergency.
• No dose adjustment is required in patients with renal impairment

Initial Argatroban Infusion Rates 

Start – 0.75 mcg/kg/min (consider maximum infusion rate of 10 mcg/kg/min)

1. In patient with usual bleeding risk
2. Without multiorgan organ failure and 
3. Normal hepatic function 

Start – 0.2 mcg/kg/min (or alternatively consider use of bivalirudin)

1. If bleeding patient or coagulopathy
2. Hepatic impairment
3. Multiorgan failure
4. Cardiopulmonary bypass 

Monitoring Therapy

• aPTT levels are used to monitor argatroban activity at PMCH.
  • Ensure age-based aPTT values for preterm infants and term infants are used.
• aPTT Monitoring
  • When initiating therapy, check the aPTT level 2 hours after the initiation of the argatroban infusion
  • Additional aPTT level monitoring are checked 2-4 hours after each dose change until the patient has reached their targeted anticoagulation level.
  • When 2 consecutive aPTT results obtained 4 hours apart are therapeutic, obtain aPTT level every 12 hours at a minimum.
• Ongoing monitoring
  • HIT patient: daily platelet count until normal and then twice weekly while on argatroban
• Check PT/INR at least twice weekly while on argatroban. Argatroban will significantly elevate PT/INR values. It is not recommended to give products for the sole purpose of correcting INR/fibrinogen unless clinically indicated.
• Check TEG as needed.
• Check fibrinogen at least twice weekly while on argatroban

 Usual Reference Range for Therapeutic Dosing

• In patients with liver dysfunction adjust in increments of ≤0.05 mcg/kg/minute
• aPTT: Goal is 1.5-3x baseline (not to exceed 100 seconds)
  • For aPTT <1.2x baseline, increase rate by 40%
  • For aPTT 1.2-1.5x baseline, increase rate by 20%
  • For aPTT 1.5-3x baseline, no change
  • For aPTT >3-4x baseline (less than 100 seconds), decrease rate by 20%
  • For aPTT >4x baseline, hold infusion for 1 hour, then recheck aPTT; decrease rate by 50% once aPTT <100 seconds

Safety Precautions

• Renal Impairment: Dose adjustment recommended 
• Hepatic Impairment: See dose adjustments above

 aPTT Considerations
aPTT may not always be representative of argatroban concentration.

Can see Increased PTT with:

• Heparin contamination (from line)
  • Kathy in special coag lab can run hepzyme assay. But for more rapid TAT, can get PT/INR or anti-Xa to identify contamination, since PT/INR won’t increase with heparin contamination alone, but will increase with bival concentration
• Traumatic phlebotomy – 
• Low fibrinogen, low Factor XII or VIII (> 30-40% depletion)
• Hemolysis – with elevated plasma free hemoglobin
• Impaired renal function with resultant increased argatroban concentration
• Lupus anticoagulant
• Vitamin K deficiency
• Disseminated intravascular coagulopathy or other coagulopathy 
• Hyperbilirubinemia

Can see Decreased PTT with: 

• High factor VIII
• Systemic Inflammation
• Activation of the contact pathway 
• Elevated fibrinogen or D-dimer
• Hypertriglyceridemia
• Hemolysis- elevated plasma free hemoglobin 
• Delay in sample analysis