Factor Concentrates

Introduction

• Factor concentrates offer targeted and rapidly acting therapies for patients with inherited and acquired bleeding disorders.¹
  • These include severe traumas, massive transfusion protocols, anticoagulant reversal, off-label usage in severe bleeding, and management of patients with rare factor deficiencies.
• Factor concentrates provide precise dosing and reduced volume transfused compared to traditional plasma-based products.
• Improvements in purification and viral inactivation processes have also made factor concentrates safer over time.
• Concentrates can be broadly divided into two categories:¹
  • Plasma-derived – extracted and purified from donated human plasma
  • Recombinant concentrates – produced through genetic engineering techniques, which significantly reduce the transmission of infection agents

Factor Concentrates

Prothrombin Complex Concentrates (PCC)²

• Indications: Reversal of warfarin, Factor II, VII, IX, X congenital deficiencies, bleeding requiring rapid replacement
• 4 – factor PCC (II, VII, IX, X): Kcentra/Beriplex, Balfaxar/Octaplex, or Cofact
• 3 – factor PCC (II, IX, X) Bebulin VH and Profilnine SD

Activated PCC^1,2

• Indications: Hemophilia A or B with inhibitors (anti-factor VIII/IX antibodies)
• FEIBA (Factor Eight Inhibitor Bypass Agent)
• Contains activated factor VII and non-activated II, IX, and X

Fibrinogen Concentrates¹

• Indications: Congenital afibrinogenemia/hypofibrinogenemia, acquired fibrinogen deficiency (trauma, obstetrics, disseminated intravascular coagulation, massive transfusion)
• Products: Fibryga (FDA approved for acquired & congenital fibrinogen deficiency), RiaSTAP, FibCLOT, Clottafact

Factor VIIa³

• Indications: Hemophilia A or B with inhibitors, Factor VII deficiency
• Plasma derived
• FEIBA (Factor Eight Inhibitor Bypass Activity) – Factor VIIa one component
• Recombinant
• NovoSeven

Factor VIII Concentrates¹

• Indications: Hemophilia A, acquired FVIII deficiency, perioperative hemostasis.
• Plasma derived
  • Can contain von Willebrand factor (vWF)
  • Examples: Humate-P, Wilate, Koate-DVI
• Recombinant
  • Standard half-life: Advate, Recombinate, Kogenate FS
  • Extended half-life: Eloctate (Fc fusion), Jivi (PEGylated), Adynovate (PEGylated)
• Emicizumab
  • Monoclonal antibody that mimics activate Factor VIIIa
  • Can be used in patients with factor VIII inhibitors (antibodies against factor VIII)

vWF Concentrates^1,4

• Indications: von Willebrand disease (vWD), acquired von Willebrand deficiency
• Plasma derived (contains Factor VIII)
  • Humate-P, Wilate, Alphanate
• Recombinant
  • Vonvendi (Requires separate Factor VIII if low)

Factor IX¹

• Indications: Hemophilia B
• Plasma derived
  • AlphaNine SD, Mononine.
• Recombinant
  • Standard half-life: BeneFIX
  • Extended half-life: Alprolix, Idelvion, Rebinyn

Factor X¹

• Indications: Factor X deficiency
• Plasma derived
  • Coagadex

Factor XI¹

• Indication: Congenital Factor XI deficiency
• Plasma Derived:
  • Hemoleven (Not available in the United States)

Factor XIII¹

• Indication: Factor XIII deficiency
• Products:
  • FXIII-A subunit (rFXIII): Tretten.
  • Plasma-derived FXIII: Corifact (FXIII-A and FXIII-B)

Clinical Applications

Congenital/Acquired Hemophilias⁴

• Routine prophylaxis to prevent spontaneous and joint bleeds (standard of care for severe disease)
• On-demand treatment of acute bleeds
• Perioperative hemostatic management for minor and major procedures
• Enhanced half-life products to reduce infusion burden

vWD

• Plasma-derived vWF/FVIII concentrates for:
  • Patients who are unresponsive or contraindications to DDAVP
  • Major surgical procedures
  • Significant or recurrent mucosal bleeding

Rare Congenital Factor Deficiencies^1,4

• Availability depends on the specific factor:
  • Factor VII (rFVIIa) for congenital FVII deficiency
  • Factor X concentrate for congenital FX deficiency
  • Factor XIII, fibrinogen (factor I), and others for rare hereditary deficiencies
  • Used for prophylaxis, acute bleeding, and perioperative management

Reversal of Anticoagulation²

• 4-factor PCC (prothrombin complex concentrate) for:
  • Rapid reversal of warfarin in major bleeding or urgent surgery
  • Emergent vitamin K deficiency bleeding
• Activated PCC is used for patients with hemophilia and inhibitors.
  • Contains activated factor VII to help with inhibitors
  • Also used in patients with uncontrolled bleeding.
• PCC is associated with faster INR reversal, less volume overload, and lower mortality versus fresh-frozen plasma (FFP) in warfarin reversal.

Perioperative Bleeding

• Factor concentrates can correct coagulopathies with less volume and more precision when compared to fresh frozen plasma
• A randomized controlled trial (RCT) (FIBRES Trial) with 735 patients undergoing cardiac surgery who developed significant bleeding and low fibrinogen levels showed that using fibrinogen concentrate was noninferior to cryoprecipitate. The average number of blood-component units transfused in the first 24 hours was nearly the same (16.3 vs 17.0 units) in the two groups.⁵
• A RCT (FARES II trial) with 420 patients undergoing cardiac surgery and requiring coagulation factor replacement for excessive bleeding showed that PCC was superior to FFP for hemostatic efficacy, with fewer serious adverse events and fewer cases of acute kidney injury.⁶
• A meta-analysis of RCTs (4 RCTs, 671 patients) comparing PCC vs FFP in cardiac surgery bleeding showed that PCC reduced red blood cell transfusion requirements and improved coagulation parameters without significant safety risks in cardiac surgery.⁷

Associated Risks

Thromboembolic Events

• There is concern for thromboembolic events, especially with overcorrection of factor deficiencies, though data can be conflicting and variable. The risk of these events can also be impacted by concomitant medications, age, comorbidities, and procedures.
• There is a questionable increase in thromboembolic events with recombinant factor VIIa. Serious events have been reported, but the rate from a retrospective analysis of clinical trials and surveillance registries was 0.17%. The rate was higher for those with acquired hemophilia receiving recombinant factor VIIa at 1.77%.³
• Comparing PCC to FFP in cardiac cases showed no significant difference in thromboembolic events.⁸
• Thromboembolic in patients receiving warfarin reversal range from around 6% to 28% after receiving PCC compared with 7% to 12% with FFP comparator groups⁹
• FIBRES study (RCT with 735 patients) compared fibrinogen concentrate to cryoprecipitate in patients undergoing cardiac surgery who developed significant bleeding and low fibrinogen levels. Thromboembolic events in the fibrinogen group were 7.0% compared to 9.6% in the cryoprecipitate group.⁵
• A systematic review of patients with hemophilia A, hemophilia B, and vWD who received factor concentrates showed a thromboembolic event rate of less than 1%¹⁰

Inhibitor Formation

• Patients with hemophilia A and B exposed to factor concentrates can develop inhibitors, antibodies against the factor concentrate, which can lead to difficulty in managing bleeding episodes or treatment failure.¹
  • Emerging antibody therapies (emicizumab) can aid in the management of these patients.

Allergic Reactions/Infections

• Overall, the rates of allergic reactions are low but vary with specific factor concentrate.
• Higher reaction rates are typically seen in plasma-derived concentrates compared to recombinant products.¹
• Rates have improved over the decades with improved virucidal and purification techniques