Clotting Factor Replacement Products

PharmacologyProthrombin complex concentrates (PCCs) and activated prothrombin complex concentrate (aPCC) are derived from pooled human plasma, and, depending on the preparation, contain differing amounts of the human clotting factors II, VII, IX, X, and proteins C and S.
1. Three-factor PCCs include factors II, IX, and X without appreciable amounts of factor VII.
2. Four-factor PCC products include factors II, VII, IX, and X as well as protein C and protein S.
3. Activated PCC (aPCC), also known as Factor Eight Inhibitor Bypassing Activity (FEIBA^® NF), contains factors II, IX, X, and activated factor VII.
4. Recombinant factor VIIa (rFVIIa, NovoSeven RT^®) is structurally similar to human plasma-derived factor VII but is cultured in animal cells and contains only activated factor VII without appreciable amounts of other clotting factors.
5. All preparations are given only intravenously and are immediately bioavailable. Their distribution is limited to the vascular space; they are likely removed from circulation by the hepatic reticuloendothial system, similar to endogenous coagulation factors.
Indications
1. Reversal of life-, limb-, or sight-threatening bleeding (eg, intracranial hemorrhage, massive GI bleed, life-threatening traumatic injury, compartment syndrome, retinal hemorrhage) in patients with acquired deficiencies of clotting factors associated with the use of vitamin K antagonists (eg, warfarin), direct thrombin inhibitors (eg, dabigatran), or factor Xa inhibitors (eg, rivaroxaban, apixaban, or edoxaban).
Contraindications
1. Previous anaphylaxis to PCC, aPCC, or rFVIIa, or any of their components.
2. Patients with a history of anaphylaxis to heparin, or history of heparin-induced thrombocytopenia (HIT), should not be given Bebulin^® VH, Octaplex^®, Beriplex^® PN, or KCentra^®. These products contain small amounts of heparin. Note: Activated PCC (FEIBA^® NF), rFVIIa (NovoSeven RT^®), and Profilnine^® SD do not contain heparin.
3. rFVIIa (NovoSeven RT^®) should not be given to patients with known hypersensitivity to mouse, hamster, or bovine proteins.
4. Octaplex^® is contraindicated in patients with IgA deficiency and known anti-IgA antibodies.
5. Prothrombin complex concentrates increase the risk of thromboembolic events when given to patients with disseminated intravascular coagulation (DIC), myocardial infarction, and pulmonary embolism and should not be given to patients with these acute conditions.
6. The risks of anaphylaxis, HIT, and thromboembolic events must be weighed against the benefits of anticoagulant reversal depending on the individual patient situation.
7. Recombinant factor VIIa should NOT be given concurrently with PCC because of a significant increased risk of thrombotic events. Note: Fresh frozen plasma has been successfully given after rFVIIa or PCC administration.
Adverse effects
1. Black box warning.
  1. KCentra^®. Serious venous and arterial thromboembolic complications have been reported in clinical trials and postmarketing surveillance.
  2. FEIBA^®NF. Thrombotic and thromboembolic events have been reported in postmarketing surveillance particularly in high doses or in patients with underlying risk factors for thrombosis.
  3. NovoSeven RT^®. Serious venous and arterial thrombotic events have been reported.
2. Other. Mild adverse effects include headache, nausea, vomiting, diarrhea, abdominal pain, dyspnea, hypertension, pain at the injection site, pyrexia, and dizziness/somnolence.
  1. Octaplex^® has been associated with a transient mild transaminitis.
  2. Reported effects of FEIBA^®NF include dysgeusia and hypoesthesia.
  3. NovoSeven RT^® use has been associated with hemorrhage, edema, and rash.
3. Infection. While products are screened for viral infections, PCC and aPCC are derived from human plasma and thus carry the risk of communicable disease. Octaplex^® has been associated with seroconversion of Parvovirus B19 titers (3 of 90 patients enrolled in clinical trials).
4. Use in pregnancy. FDA Category C. No sufficient human studies exist to determine the safety of PCC, aPCC, or rVIIa in pregnancy. Pregnant women receiving PCC or aPCC should be advised of the risk of possible communicable infections.
Drug or laboratory interactions. No clear laboratory interactions have been identified. However, three- and four-factor PCCs contain small amounts of heparin, and this should be taken into account when interpreting coagulation studies.
Dosage and method of administration
1. PCCs and aPCC. See Table III-6 for reversal of vitamin K antagonists based upon initial INR. Note that aPCC is not recommended for reversal of vitamin K antagonists because the risk of thrombosis may be greater. See Table III-7 for reversal of direct thrombin inhibitors and factor Xa inhibitors.
2. Recombinant factor VIIa (Novoseven RT^®). There is no consensus on the dosing of rVIIa for the reversal of vitamin K antagonists, direct thrombin inhibitors, or factor Xa inhibitors. A single dose of 1,200 mcg has been recommended for reversal of vitamin K antagonists, while a dose of 120 mcg/kg has been recommended for reversal of dabigatran.

TABLE III-6. DOSES FOR REVERSAL OF VITAMIN K ANTAGONISTS (eg, WARFARIN, “SUPERWARFARINS”) BASED ON INR

	INR 2.0-2.4	INR 2.5-2.9	INR 3.0-3.4	INR 3.5-3.9	INR 4.0-5.9	INR ≥6	Maximum Dose
Four-factor PCCs^a,b
Octaplex^®	22.5 U/kg	32.5 U/kg	40 U/kg	47.5 U/kg	47.5 U/kg	47.5 U/kg	3,000 U
Beriplex^®	25 U/kg	25 U/kg	25 U/kg	25 U/kg	35 U/kg	50 U/kg	5,000 U
KCentra^®	25 U/kg	25 U/kg	25 U/kg	25 U/kg	35 U/kg	50 U/kg	5,000 U
Three-factor PCCs^a
Profilnine^®	50 U/kg	50 U/kg	50 U/kg	50 U/kg	50 U/kg	50 U/kg	50 U/kg
Bebulin^®	50 U/kg	50 U/kg	50 U/kg	50 U/kg	50 U/kg	50 U/kg	50 U/kg

^aFour-factor PCC is the preferred agent; if unavailable, then give three-factor PCC with 10-15 mL/kg of fresh-frozen plasma (FFP). If unable to give PPC or FFP, consider recombinant factor VIIa (rFVIIa) in a single dose of 1,200 mcg. All patients should receive one dose of vitamin K unless contraindicated (see Vitamin K₁ (Phytonadione)).

^bAlthough fixed-dose regimens of 500-1500 U have been studied, weight- and INR-based dosing is recommended.

TABLE III-7. DOSES OF CLOTTING FACTOR COMPLEXES FOR REVERSAL OF DIRECT ACTING ORAL ANTICOAGULANTS^a

	Dose	Maximum Dose
Activated PCC^b
FEIBA^®	25-100 U/kg	100 U/kg in a single dose
Four-factor PCCs^c
Octaplex^®	50 U/kg	3,000 U
Beriplex^®	50 U/kg	5,000 U
KCentra^®	50 U/kg	5,000 U
Three-factor PCCs
Profilnine^®	50 U/kg	50 U/kg
Bebulin^®	50 U/kg	50 U/kg

^aSpecific reversal agents have been developed for dabigatran (idarucizumab) and the factor Xa inhibitors (andexanet alfa), and if available, these should be given first.

^bAPCC is the preferred clotting factor complex for direct thrombin inhibitors (eg, dabigatran) if idarucizumab is unavailable or insufficient to stop bleeding. If APCC not available, give a four-factor PCC potentially in combination with rFVIIa. If neither of these is available, give a three-factor PCC with 10-15 mL/kg of fresh-frozen plasma (FFP). Consider recombinant factor VIIa (rFVIIa) if unable to give a PCC or FFP.

^cFour-factor PCC is the preferred clotting factor complex for factor Xa inhibitors. If not available, give a three-factor PCC with FFP. If neither of these is available, give FFP alone. Consider recombinant factor VIIa (rFVIIa) if unable to give a PCC or FFP.

section name header

Introduction