PROTHROMBIN COMPLEX INJ,LYPHL
Clinical Criteria Summary
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Exclusion Criteria
- Patient with disseminated intravascular coagulation (DIC)
- History of heparin-induced thrombocytopenia (HIT)
- History of anaphylactic or severe systemic reaction to 4F-PCC or any components (heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III, human albumin)
- Situation in which administration of intravenous vitamin K and withdrawal of warfarin therapy alone would adequately reverse anticoagulation within the required timeframe for an urgent invasive procedure or surgery
- Patients in whom complete correction of International Normalized Ratio (INR) is not clinically appropriate or necessary
Inclusion Criteria
- Receiving treatment with a vitamin K antagonist (e.g., warfarin) therapy with INR ≥ 2 AND standard measures for bleeding cessation/reversal are contraindicated or insufficient
- Co-administration with vitamin K is required
- PLUS ONE of the following indications:
- Acute life-threatening major bleeding (including intracranial hemorrhage)
- Need for urgent life-saving surgery or invasive procedure
Dosage and Administration
- Administered as a single dose IV infusion based on pre-treatment INR and actual body weight
- Dosing calculated based on the quantity of factor IX in the product (varies by vial potency)
- Pre-treatment dosing table:
- INR 2 to <4: 25 IU/kg (Maximum dose: 2500 IU)
- INR 4 to 6: 35 IU/kg (Maximum dose: 3500 IU)
- INR >6: 50 IU/kg (Maximum dose: 5000 IU)
- Dosing based on actual body weight up to 100 kg; do not exceed maximum doses for patients weighing >100 kg
- Do not mix with other products; administer through a separate infusion line
- Administer at a rate of 0.12 mL/kg/min, up to a maximum rate of 8.4 mL/min
- No blood should enter the syringe (risk of fibrin formation)
- Repeat dosing is not recommended as effectiveness and safety have not been established
Monitoring
- Use a current, pre-treatment INR taken close to the time of 4F-PCC dosing due to potential fluctuations in acute bleeding or urgent settings
- Evaluate laboratory coagulation parameters alongside clinical signs of hemostasis and thromboembolism post-administration
Clinical Considerations & Risk Management
- Thromboembolic Risk: Carries a Boxed Warning for arterial and venous thromboembolic complications. High-risk populations excluded from trials include patients with recent history (within last 3 months) of thrombotic event, myocardial infarction, cerebrovascular accident, transient ischemic attack, unstable angina pectoris, severe peripheral vascular disease, or DIC; known antiphospholipid syndrome; known inhibitors to coagulation factors II, VII, IX, or X; and known hereditary protein C or protein S deficiency.
- Non-warfarin Oral Anticoagulants: Insufficient clinical evidence for off-label use; not FDA approved. Consider only in severe, life-threatening situations where all other measures have failed or are not indicated. Weak preference noted for activated PCC (FEIBA) for dabigatran reversal and 4F-PCC for rivaroxaban/apixaban reversal.
- Fluid Status: Associated with a numerically lower rate of fluid overload or cardiac events compared to plasma. Mean infused volume <100 mL. May be preferred if patient cannot tolerate additional plasma volume.
- Timing of Reversal: Superior INR correction at 30 minutes to 12 hours post-infusion compared to plasma; difference not evident at 24 hours. Preferable for rapid reversal within 24 hours (e.g., intracranial hemorrhage, life-threatening bleeding, urgent surgery). No significant difference in effective hemostasis at 24 hours, mortality, or length of hospital stay.
- History of HIT: Contains heparin; history of HIT is a contraindication per FDA labeling. May be considered if patient has negative antibody testing for life-threatening bleeding requiring cardiac surgery (per ACCP guidelines), though evidence is limited.
- Infectious Disease Transmission: Blood-derived product carries infection risk despite two virus reduction steps.
- Pregnancy and Childbearing Potential: Reserve for life-threatening instances; weigh risks and benefits to mother and fetus. Category C; not studied in pregnancy.
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General Principles & Supportive Care
- Reversal agents considered ONLY for severe, life-threatening bleeding where potential risk of thromboembolism is deemed less than consequences of continued bleeding.
- DOACs have relatively short half-lives; bleeding often managed by temporarily discontinuing anticoagulant and providing supportive care.
- Supportive care includes: discontinuing anticoagulant, maintaining adequate diuresis, compression, surgical repair, fluid and/or blood replacement, hemodynamic support (hemodialysis for dabigatran).
- Consider activated charcoal for known recent DOAC ingestion within past 2-4 hours.
- Consider presence of other antithrombotic drugs (e.g., antiplatelet agents) and discontinue as appropriate.
- Use reversal agents reserved for patients with known recent exposure to a DOAC.
- Restart anticoagulant therapy as soon as medically appropriate due to elevated risk of thromboembolism.
Idarucizumab (Praxbind) Criteria
- Indication: Reversal of dabigatran in setting of bleeding or emergent surgery/urgent procedures.
- Inclusion Criteria (ALL required):
- Patient taking dabigatran with provider reasonably certain therapeutic anticoagulant levels are present.
- Life-threatening or critical site bleeding (e.g., ICH) OR need for truly emergent procedure that cannot be delayed ≥8 hours requiring normal hemostasis.
- Standard measures for bleeding management (e.g., discontinuing anticoagulant, compression, surgical repair, fluid/blood replacement, hemodynamic support) are insufficient.
- Patient’s risk of thromboembolism deemed less than consequences of continued bleeding or delay of procedure/surgery.
- Safety & Considerations:
- Specific for dabigatran only; will not reverse effects of other anticoagulants including Factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban).
- Thromboembolic events reported (4.8% within 30-day follow-up in REVERSE-AD); consider restarting anticoagulant as soon as medically appropriate (dabigatran can be started 24 hours after administration).
- Hypersensitivity reactions reported.
- Hereditary fructose intolerance due to sorbitol excipient (4g per dose) requires consideration of combined metabolic load.
- Re-elevation of coagulation parameters observed in limited patients; safety/effectiveness of repeat doses not established.
4-Factor Prothrombin Complex Concentrate (4F-PCC/KCetra) Criteria
- Indication: DOAC-associated life-threatening bleeding or need for emergent surgery/urgent procedures (Off-label).
- Exclusion Criteria (ANY present = NOT receive):
- Known anaphylactic or severe systemic reaction to 4F-PCC or components (heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III, human albumin).
- Disseminated intravascular coagulation.
- History of heparin-induced thrombocytopenia (contains heparin).
- Inclusion Criteria (ALL required):
- Patient taking a DOAC with provider reasonably certain therapeutic anticoagulant levels are present.
- Specific reversal agent FDA approved for patient’s condition is not readily available.
- Life-threatening or critical site bleeding (e.g., ICH) OR need for truly emergent procedure that cannot be delayed requiring normal hemostasis.
- Standard measures for bleeding management are insufficient.
- Patient’s risk of thromboembolism deemed less than consequences of continued bleeding or delay of procedure/surgery.
- Safety & Considerations:
- Boxed warning for arterial and venous thromboembolic complications; higher thromboembolic events vs plasma in VKA trials, especially with history of thromboembolism.
- Not suitable for patients with thromboembolic events in prior 3 months.
- Hypersensitivity reactions observed.
- Risk of transmitting infection from human blood source.
- No FDA-approved products indicated for reversal of apixaban, rivaroxaban, or edoxaban; use of nonspecific agent such as 4F-PCC may be considered though evidence is limited. If 4F-PCC unavailable, activated PCC (aPCC/FEIBA) may be considered.
Dosing & Administration
- Idarucizumab: Single dose 5 gm (2 vials x 2.5 gm). Administered IV as 2 consecutive infusions or bolus injection. Requires refrigeration.
- 4F-PCC: Doses vary: single dose 25-50 units/kg or fixed dose 2,000 units IV. Dosing calculated based on quantity of factor IX in product. Administered by IV infusion at rate up to 8.4 ml/min (~210 units/min). Supplied in 500 or 1000 unit vials requiring reconstitution; store at 2-25°C.