Hemophillia Flashcards
What is hemophilia?
Genetically inherited bleeding disorder
What genes are affected and where is it located?
Genes for factor VIll and IX located on the x chromosome
What is the root cause for hemophilia
Low or no production of particular clotting factors
What are the types of hemophilia
Hemophilia A: factor VIll deficiency
Hemophilia B: factor IX deficiency
Acquired hemophilia: autoantibody against VIII
What are hemophilia complications?
Joint damage/disease
Risk for viral infections
Inhibitor/ neutralizing antibodies
Heart disease, high blood pressure
Joint damage/ disease
Chronic bleeding at joints
Risk of viral infections
HIV
Hepatitis
Inhibitor/ neutralizing antibodies
30% gf hemophilia A patients develop abs
Heart disease/HBP
Caused partly by inability to be active
Hemophilia therapeutics
Plasma transfusion of low concentrations of clotting factors
How was plasma concentration of clotting factors improved
Cryopercipitation
What was the major concern for increased plasma concentration of clotting factors through cryopercipitation
Neutralizing antibodies produced in the body
Cryoprecipitate factor VIll
Treat hemophilia A
What is the major concern for the use of cryoprecipitate factor VIll
Caries risk of viral infection
How is cryoprecipitate factor VIll prepared
From a single donor and whole blood
Why was cryoprecipitate factor VIll preferred over lypholized
Lypholization disrupts the polymeric structure of factor VIll and it requires pooling from multiple homers
Lyophilized factor IX
Treatment of hemophilia B
How is lyophilized factor IX prepared
Extracted from plasma, most inactive protein but can still activate clotting factors
Why is heparin added for patients taking lyophilized factor IX
To limit thrombin overactivation
What is mononine?
Monoclonal antibody specific to factor IX to cleanly isolate the targeted factor IX which is separated from antibody and undergoes further purification
How is monomine prepared and administered?
Pooled from human plasma and administered via IV
Which patient is administered NovoSeven (rFactor VIIa)
Patient with VIl deficiency and treatment of bleeding episodes in hemophilia
What is the MOA of NovoSeven
Increases thrombin activity activity for both type A and B
How is NovoSeven prepared?
Human gene recombinantly expressed in baby hamster kidney cells
Secreted protein is cleaved to its VIIa active form
Packaged in lyophilized single use vial (IV)
What is NoveSeven RT
Room temperature stable formulation of NovoSeven
Obizur (r porcine factor VIll): what type of hemophilia is it used for?
A
Obizur is what kind of therapeutic
Antibody with a 90 kD heavy chain and 80 kD light chain
How is obizur produced?
Expressed in hamster kidney cells and affinity for purified
Obizur half life
11 hours
How is obizur packaged and administered
Packaged lyophilized
Administered IV
True or false: obizur has a comparable activity to human factor VIII
True
Eloctate (r Factor VIII- Fc fusion protein) is approved for the treatment of what type of hemophilia
A
What type of therapeutic is eloctate?
Analog of hFactor VIII covalently linked to human lgG
When the IgG region of eloctate binds to an IgG receptor, what occurs?
There is a delay in lysosomal degradation of IgG by returning them to circulation
Eloctate half life
16-20hrs
How is eloctate produced?
Expressed in HEK cells and purified
How is eloctate-packaged and administered
lyophilized and IV
Nuwiq (r human factor VIIII; truncated) is approved for the treatment of what type of hemophilia
A
What is the characteristic of nuwiq
Contains heavy and light chain that lacks a b-domain
True or false: Nuwiq heavy and light chain not are covalently attached
True
Nuwiq half life
17 hours
How is Nuwiq produced
HEK cells and purified
How’s Nuwiq packaged and administered
lyophilized and IV
Kovaltry (r human factor VIll) is approved for what type of hemophilia?
A
What type of therapeutic is kovaltry?
Unmodified full length human factor VIII
How is kovaltry produced?
Express in hamster kidney cells and co-expressed with HSP70 proper folding
Kovaltry half life
12 hrs
How is kovaltry packaged and administered?
Lyophilized and IV
Aystyla (r single chain factor VIII) is approved for what type of hemophilia
A
How’s afstyla designed
Single chain with heavy and light chain covalently linked
What clotting factor does afstyla increases its stability and has affinity for?
Von willebrand factor
What is the function of Von willebrand factor?
Prevents degradation of factor VIII
What other uses are there for afstyla?
Hemophilia A bleeding episodes
Routine prophylaxis
preop treatment
Afstyla half life
14 hours
How is afstyle prepared and administered
Lyophilized and IV
How is hemlibra (emicizumab) used in hemophilia theragry
It is a bispecific antibody that targets factor IXa and X and used as prophylaxis to reduce hemophilia A bleeding events, for patients with or without factor VIll inhibitors
What are other uses of hemlibra
Swelling and joint pain
What is the black box warning for hemlibra
Thrombotic microangiopathy and thrombotic events
What is esperoct (anti-hemophilic factor, glyopegylated- exei) used for
Hemophilia A
What is esperoct
Factor 8 analog linked to PEG (40 kD), used to prevent or reduce bleeding episodes of hemophilia A
Why does esperoct have PEG
It increases half life and reduces clearance
Esperoct half life
21.7 hrs
Aprolix (Factor IX-Fc fusion protein) use?
Hemophilia B
What type of therapeutic is alprolix
Recombinant factor IX fused to Fc fusion protein (IgG)
Delays degradation and increases half-life
How is alprolix produced?
Expressed in HEK cells and purified
Alprolix half life
86 hours
Idelvion (r Factor IX fused to albumin) hemophilia type
B
Idelvion therapeutic type
Genetic fusion of human factor IX and human
albumin; expressed as a single protein
Idelvion mechanisms action
Circulates as fusion protein until factor IX is
activated
Albumin is cleaved from factor IX only
when it is needed for clotting
Idelvion half life
90 hours
Rebinyn (Factor IX, GlycoPEGylated) Hemophilia type
B
Rebinyn (Factor IX, GlycoPEGylated) therapeutic type
Factor IX is glycoPEGylated to increase
circulating half-life of Factor IX
Rebinyn (Factor IX, GlycoPEGylated) Half life
118 hours
Rebinyn (Factor IX, GlycoPEGylated) Modification causes
Lower bleeding frequency and less frequent IV dosing
What is the only reconstituted IV
Idelvion (r Factor IX fused to albumin)
