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.
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.
FFPs, PCCs
Factors II, VII, IX, and X require vitamin K as a cofactor for their synthesis by the liver.
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.
Strategy of expression of recombinant FVIII in transgenic animals
Full-length FVIII cDNA is fused with the regulatory sequence of a milk specific protein (WAP, whey acidic protein) to target FVIII secretion into milk. Transgenic pigs are obtained by microinjection of the hybrid DNA into the fertilized oocyte, and FVIII-encoding cDNA is randomly integrated into the genome of recipient sows. Newborns carrying FVIII DNA are analyzed for the presence of FVIII
protein in milk and its functional activity.
Combinations of factor products available
Desmopressin (DDAVP)
- Desmopressin acetate increases the factor VIII
activity of patients with mild hemophilia A or von Willebrand disease. It can be used in preparation for minor surgery such as tooth extraction without any
requirement for infusion of clotting factors if the patient has a documented adequate response. High-dose intranasal desmopressin is available and has been shown to be efficacious and well tolerated by patients.
Emicizumab - overview + moa
- Emicizumab is a novel bispecific monoclonal antibody
to factor IXa and factor X that replaces the function of factor VIII. - The drug is FDA-approved to prevent or reduce the
frequency of bleeding episodes in adult and pediatric
patients with hemophilia A (congenital factor VIII
deficiency) with or without factor VIII inhibitors. - Clinical studies have shown a dramatic reduction in
bleeding events in hemophilia patients with or without Factor VIII inhibitors. - The dose is 3 mg/kg subcutaneously daily for 1 week
(loading dose), followed by 1.5 mg/kg every week, 3
mg/kg biweekly or 6 mg/kg monthly. The bioavailability is 80–90% after subcutaneous injection, and the half-life is approximately 27 days. - Thrombosis has been reported in patients also
receiving prothrombin complex concentrates. Emicizumab will interfere with standard PTT and PTT-based factor assays. Chromogenic factor VIII assays using bovine components are available to assess endogenous factor VIII levels in patient treated with emicizumab.
Overview of licensed and investigational (italics) therapies to treat hemophilia A or B with or without inhibitors. Factor replacement therapies (green), gene or cellular
therapies (red), substitutive therapies (purple), and rebalancing therapies (blue)
