24 - Factor Replacement Therapy: Pharmacology Flashcards
Clotting and factor dyregulations: general pharmacology principles
Factors in the coagulation cascade
Coagulation Disorders & Replacement Sources
Factor I deficiency: common name, deficiency state name, half-life of factor, and replacement source
Factor II deficiency: common name, deficiency state name, half-life of factor, and replacement source
Factor V deficiency: common name, deficiency state name, half-life of factor, and replacement source
Factor VII deficiency: common name, deficiency state name, half-life of factor, and replacement source
Factor VIII deficiency: common name, deficiency state name, half-life of factor, and replacement source
Factor IX deficiency: common name, deficiency state name, half-life of factor, and replacement source
Factor X deficiency: common name, deficiency state name, half-life of factor, and replacement source
Factor XI deficiency: common name, deficiency state name, half-life of factor, and replacement source
Von Willebrand deficiency: common name, deficiency state name, half-life of factor, and replacement source
Factor XIII deficiency: common name, deficiency state name, half-life of factor, and replacement source
Other medications for other factor deficiencies
- Factor XIII is a transaminase that crosslinks fibrin within a clot, thereby stabilizing it. Congenital factor XIII deficiency is a rare bleeding disorder. Recombinant factor XIII A-subunit is FDA-approved for prevention of bleeding in patients with factor XIII deficiency.
- Factor X concentrate is a plasma-derived factor X preparation that is FDA-approved for control of bleeding in patients with factor X deficiency and for perioperative management of patients with mild factor X deficiency.
- Protein C concentrate is a plasma-derived protein C preparation approved for treatment of life threatening thrombosis or purpura fulminans, a life-threatening disorder involving thrombosis in skin and systemic circulation.
- Recombinant antithrombin is FDA-approved for prevention of perioperative and peripartum thromboembolic events in patients with hereditary antithrombin deficiency.
Factor Deficiency—Factor Replacement
- Factor VIII deficiency (classic hemophilia, or hemophilia A) and factor IX deficiency (Christmas disease, or hemophilia B) account for most of the heritable coagulation defects.
- Concentrated plasma fractions and recombinant protein preparations are available for the treatment of these deficiencies.
- Administration of plasma-derived, heat- or detergent-treated factor concentrates and recombinant factor concentrates are the standard treatments for prevention and treatment of bleeding associated with hemophilia.
- Lyophilized factor VIII concentrates are prepared from large pools of plasma. Transmission of viral diseases such as hepatitis B and C and HIV is reduced or eliminated by pasteurization and by extraction of plasma with solvents and detergents. However, this treatment does not remove other potential causes of
transmissible diseases such as prions. - For this reason, recombinant clotting factor preparations are recommended whenever possible for factor replacement.
- The best use of these therapeutic materials requires diagnostic specificity of the deficient factor and quantitation of its activity in plasma.
Blood Factors
Center for Biologics Evaluation and Research (CBER)
* Regulates the collection of blood and blood components used for transfusion or for the manufacture of pharmaceuticals derived from blood and blood components, such as clotting factors
- Establishes standards for the products
FDA has progressively strengthened the overlapping safeguards that protect patients from unsuitable blood and blood products - Blood donors asked specific & direct questions about risk factors for a transmissible disease
- “Up-front” screening eliminates approximately 90 percent of unsuitable donors
- Requires blood centers to maintain lists of unsuitable donors
- Blood donations are tested for seven different infectious agents FDA has significantly increased its oversight of the blood industry:
- FDA inspects all blood facilities at least every two years, and
- “Problem” facilities are inspected more often.
- Blood establishments are now held to quality standards comparable to those expected of pharmaceutical manufacturers.
Factor Products
Human derived Products - Fresh Frozen Plasma (FFP) - Source and production
The separation of a 450-mL (~one pint) unit of donor blood into packed red cells (RBC), platelet concentrate, and FFP
Prothrombin complex concentrates. PCC are produced
by ion-exchange chromatography from the cryoprecipitate supernatant of large plasma pools
after removal of antithrombin and factor XI.
Fresh Frozen Plasma (FFP) - Overview and use
- Contains stable coagulation factors and plasma proteins: fibrinogen, antithrombin, albumin
- Usual source of the vitamin K-dependent factors and is the only source of factor V
- Also proteins C and S
- Increases coagulation factors by ~2%
- Indications:
- Correction of coagulopathies, including the rapid reversal of warfarin
- Supplying deficient plasma proteins
- Treatment of thrombotic thrombocytopenic purpura
- Dosing: typically 15-20 mL/kg
- FFP is an acellular component and does not transmit intracellular infections, e.g., cytomegalovirus (CMV)
- Fresh frozen plasma is used for factor deficiencies for which no recombinant form of the protein is available.
Cryoprecipitate: “cryo”
FFP thawed between 1-6 C, centrifuged, and refrozen
Plasma protein fraction from whole blood
Used mostly for fibrinogen deficiencies
Each unit (~10-15mL) provides:
* Factor I (fibrinogen) 150-250 mg with a half-life of 100-150 hours
* Factor VIII 80-150 units with half-life of 12 hours
* von Willebrand factor 100-150 units with half-life of 24 hours
* Factor XIII 50-75 units with half-life of 150-300 hours
Also contains fibronectin; however there are no clear indications for fibronectin replacement.
PCCs
*Prothrombin complex concentrate (PCC)
*Prothrombin complex concentrate (PCC)
* 3 factor PCCs
* Bebulin, Profilnine: II, IX, X
* Approved for factor IX deficiency
- 4 Factor PCCs
- Kcentra: II, VII, IX, X
- Reversal of warfarin anticoagulation in patients with acute major bleeding or need for an urgent surgery
*Activated prothrombin complex concentrates (Anti-inhibitor coagulant complexes): II, IX, X and VIIa
* FEIBA (for hemophilia A and B)
* Autoplex T (for hemophilia A and B)
FFPs, PCCs
Factors II, VII, IX, and X require vitamin K as a cofactor for their synthesis by the liver.
PCCs with activated clotting factors - special
Some PCCs contain activated clotting factors, which has led to their use in treating patients with inhibitors or antibodies to factor VIII or factor IX.
Two products are available expressly for this
purpose:
– Autoplex -T
– FEIBA (Factor Eight Inhibitor Bypass Activity)
These products are not uniformly successful in arresting hemorrhage, and the factor IX inhibitor titers often rise after treatment with them.
Acquired inhibitors of coagulation factors may also be treated with porcine factor VIII (for factor VIII inhibitors) and recombinant activated factor VII. Recombinant activated factor VII (NovoSeven) increasingly is being used to treat coagulopathy associated with liver disease and major blood loss in trauma and surgery.
These recombinant and plasma-derived factor concentrates are very expensive, and the indications for them are very precise. Therefore, close consultation with a hematologist knowledgeable in this area is essential.
Recombinant Factor
Products - Recombinant FVIII-Fc manufacturing
- The coding sequences for human FVIII and the Fc region of the human IgG1 (hinge and CH2 and CH3 domains) were obtained
- HEK 293H cells (Invitrogen, Carlsbad, CA) were stably transfected with an expression vector
- Transfected HEK 293H cells were grown in
serum-free medium. - Clonal cell lines were derived and the
optimal cell line was selected based on
considerations for rFVIIIFc monomer productivity, rFVIIIFc
activity (measured by chromogenic assay), superior cell growth properties, and stability. - Cell lines with optimal characteristics were then sub-cloned by limiting dilution and further characterized to select the production clonal cell line for manufacturing.
- The clonal cell line that was selected for manufacturing was expanded to create a research cell bank (RCB).
- The RCB was expanded to create the master cell bank (MCB) from which a working cell bank (WCB) was derived.
