CHAPTER 3-19: CLOTTING FACTOR REPLACEMENT PRODUCTS

INTRODUCTION

1. Pharmacology

   Prothrombin 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 Cs and S.

   3. 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.

2. 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).

3. 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 the 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. NovoSeven^® 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 administration.

4. 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 ...