Adverse Effects

• Bleeding, caution in hepatic impairment

Purpose
To provide details about argatroban use during the hospital admission
 
Background
Specific and reversible DTI irrespective of antithrombin. Binds to thrombin active site (unlike bivalirudin which binds both circulating and clot-bound thrombin via catalytic and anionic exosite)
 
Indication
Heparin-induced thrombocytopenia
USE

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

Pharmacokinetics

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 Dosin

• 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

Perioperative Management

• Decision making regarding whether anticoagulation needs to be held depends on type of surgery and balance of bleeding versus thrombosis risk. If it is indicated, argatroban should be held for 2 hours prior to procedure.
• Restart argatroban infusion after the procedure as soon as adequate hemostasis has been established and once cleared by the surgeon or interventionist.

 
Bleeding Precautions & Warnings

• While on anticoagulation avoid aspirin, ibuprofen, or other anti-platelet drugs unless specifically indicated as anti-platelet therapy.
• Avoid IM injections, lumbar punctures, arterial punctures unless clinically deemed necessary. Apply pressure after venipuncture until bleeding has ceased.

 
Reversal Information

• There is no reversal agent. Turn off infusion when reversal is indicated.
• For intractable/refractory bleeding, give fresh-frozen-plasma (FFP) in an attempt to competitively antagonize the thrombin inhibition. Prothrombin complex concentrates (PCC) or cryoprecipitate may be considered.

Transition Information
 

From	To	Action
Argatroban	Bivalirudin/ Dalteparin/ Enoxaparin/ Fondaparinux/ Heparin	Initiate parenteral anticoagulant within 2 hours after discontinuation of argatroban
	Apixaban/ Betrixaban Dabigatran/ Edoxaban/ Ravaroxaban	Initiate apixaban, betrixaban, dabigatran, edoxaban, or rivaroxaban within 2 hours after discontinuation of argatroban infusion
	Warfarin	Argatroban must be continued when warfarin is initiated and co-administration should continue for at least 5 days. Do NOT give loading dose of warfarin. There is potential for combined effects on INR with the co-administration of argatroban and warfarin. Initiate warfarin at a low maintenance dose (maximum of 5 mg unless patient was stable on prior doses > 5 mg). Obtain daily INR with co-administration of argatroban and warfarin, and adjust warfarin dose for approximate INR goal of *4-5 during the first 5 days of concomitant argatroban and warfarin therapy.  After 5 days of co-therapy with warfarin and argatroban, decrease argatroban rate to 2 mcg/kg/min (if >2 mcg/kg/min) and check INR: If INR ≥4, discontinue argatroban and recheck INR in 4-6 hours If INR within desired therapeutic range, discontinue argatroban infusion and continue warfarin as per warfarin dosing guidelines If INR < desired therapeutic range, resume argatroban infusion and previous rate and increase warfarin dose per warfarin guideline. Recheck INR daily as above. *Note, the above target INR when on combined therapy may vary from patient to patient, but in general need to typically target a higher INR during the switch. Can also consider chromogenic factor X (<30-45%), which predicts an INR of 2.0 or higher.

 
 
Pregnancy
Currently, only Lovenox (enoxaparin) and unfractionated heparin are advised for use in pregnant women. 

References

1. Argatroban. Micromedex Solutions [Internet database]. Greenwood Village, CO: Truven Health Analytics; Accessed October 12, 2023.
2. Young G, Boshkov LK, Sullivan JE, Raffini LJ, et al. Argatroban Therapy in Pediatric Patients Requiring Nonheparin Anticoagulation: An Open-Label, Safety, Efficacy, and Pharmacokinetic Study. Pediatr Blood Cancer 2011; 56: 1103 – 1109.
3. Austin JH, Stearns CR, Winkler AM, Paciullo CA. Use of chromogenic factor X assay in patients transitioning from argatroban to warfarin therapy. Pharmacotherapy 2012;32(6):493-501.
4. Elagizi S, Davis K. Argatroban Dosing in Obesity. Thrombosis Research 2018; 163:60-63
5. Argatroban. Lexi-Drugs AHFS Drug Information [Internet database]. Lexi-Comp, Inc.; Accessed October 12, 2023.
6. Alsoufi B, Boshkov LK, Kirby A, Ibsen L, Dower N, Shen I, Ungerleider R. Heparin-induced thrombocytopenia (HIT) in pediatric cardiac surgery: an emerging cause of morbidity and mortality. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2004;7:155-71. doi: 10.1053/j.pcsu.2004.02.024. PMID: 15283365.
7. Monagle P, et al. Antithrombotic Therapy in Neonates and Children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines. Chest 2012; 141(2_suppl):e737S-e801S
8. Boshkov LK, Kirby A, Shen I, Ungerleider RM. Recognition and management of heparin-induced thrombocytopenia in pediatric cardiopulmonary bypass patients. Ann Thorac Surg. 2006 Jun;81(6):S2355-9. doi: 10.1016/j.athoracsur.2006.02.075. PMID: 16731103.