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Lecture 2

PATH 310 Lecture Notes - Lecture 2: Bispecific Monoclonal Antibody, Recombinant Dna, Thrombophilia


Department
Pathology and Molecular Medicine
Course Code
PATH 310
Professor
Christine Hough
Lecture
2

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- The extrinsic pathway is switched off with
TFPI (Tissue Factor Pathway Inhibitor)
after the pathway is started.
* This pathway is regulated with a
negative inhibitor
- The intrinsic pathway is an amplification
pathway in which thrombin is used as
positive feedback
PROCOAGULANT COMPELX FORMATION (Intrinsic tenase complex)
- Blood coagulation does not occur in the fluid phase but is limited to phospholipid
surfaces, present to areas of vessel damage and surfaces of endothelial cells
- Complexes usually involved an enzyme, cofactor, and substrate
- The complex produces the next enzyme in the cascade of blood coagulation
Enzyme FIXa
Cofactor FVIIIa
Substrate FX
5-50% mild hemophilia
1-5% moderately severe
hemophilia
<1% severe hemophilia
CLINICAL COMPLICATIONS
1. Spontaneous bleeding
- Joints (ankles, knees, elbows)
- Soft tissues
* At plasma levels lower than 5%
spontaneous bleeding occurs
frequently
2. Provoked bleeding
- Trauma (accidents, falls)
- Surgery, dental procedures
3. Critical bleeding events rare
FACTOR VIII/IX REPLACEMENT
Must be administered intravenously and can be derived from
1. Donated human plasma
Potential complications…
- Transmission of infectious agents: prions, unknown agents
- Anti-FVIII antibody generation (30% incidence)
- Anti-FIX antibody generation (3%)
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2. Recombinant protein production
Limitations include…
- Consistent supply, FVIII antibody development, Cost
HEMOPHILIA TREATMENT APPROACHES
1. On demand at time of bleeding
2. Prophylactic to prevent bleeding
It was seen that the preventative (prophylactic) method decreased the amount of join
hemorrhages and the overall number of hemorrhages
* The goal of current hemophilia treatment is the maintain therapeutic levels of FVIII/FIX
for a sustained period of time
- 100% levels are not needed for protection
- FVIII levels between 1-5% prevent spontaneous bleeding
- >10% any unprovoked bleeds are rare
* Limitation is that Factor VIII has a half-life of 12 hours
* Factor IX has a half-life of 24 hours
1. CHEMICAL MODIFICATION WITH POLYMERS
- Covalently added recombinant proteins (polymers of the hydrophilic molecule PEG)
- This provided a water cloud around the protein, which interfered with the way FVIII normally
cleared from the circulation
- This helped FVIII stay longer in circulation
- However, over PEGylation is bad because it then interferes with the interaction with the
intrinsic tenase complex
2.ADDITION OF TFPI INHIBITOR
- Addition of antibodies, peptides, aptamers that inhibit TFPI
- Causes the resoration of the production of fibrin through the extrinsic pathway
* Ab for TFPI inhibition can last for 2 to 3 weeks
3. FVIIA BYPASS ACTIVITY
- Adding in a dosage of FVII also initiates the extrinsic pathway
- The addition of the protein overcomes the blockage that occurs in the extrinsic pathway
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