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Therapeutic

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Sineshaw Mulugeta
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4 views28 pages

Therapeutic

Uploaded by

Sineshaw Mulugeta
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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Therapeutic uses of

Blood Products and


Enzyme Therapeutics
Blood and Blood Products

Source of traditional biologics


Blood composed of
oRed blood cells
oWhite blood cells
oPlatelets
oPlasma (contain cellular elements) -
therapeutic proteins come from
plasma
Therapeutic Blood Products

Clotting factors
• Factor VIIa VIII, IX and XIII
Platelet concentrate
Hemoglobin
whole blood (hemorrhage)
Red blood cells
Risk with Blood Product Use

• Transmission of infectious diseases


• Hepatitis B and C
• HIV
• Cytomegalovirus (CMV) (cold symptoms
or more serious in people with HIV)
• Treponema pallidum (syphilis)
• Trypanosomes
Guidelines for using blood
products
• Careful screening of all donors and
donations
• Use of pathogen removing methods or
inactivation during processing steps
• Stringent screening of all finished
products
• TRACEABILITY important! - no test 100%
accurate (1/42,000 HIV negative blood
unit donated is actually positive)
Use of Platelets

• Key role in blood clotting process

• Administered either prophylactically or


therapeutically to prevent or minimize blood
loss- people suffering from
thrombocytopenia (low number of
thrombocytes, alternate word for platelets)
Human Serum Albumin (HSA)

• Most abundant blood protein.


• 65.5 kDa protein
• 60% of total plasma protein
• Responsible for most of blood osmotic
pressure (retaining sufficient fluid in
blood vessels)
• makes blood “thicker than water”
Therapeutic HSA

• Available in aqueous form or

concentrated form

• Plasma extender in hemorrhage, shock,

burns and edema

• Used after surgery


Hemostasis

• Maintain constant blood volume;


• Mechanisms for hemostasis:
• Congregation and clumping of platelets at
site of vascular injury
• Localized constriction of blood vessel at
damage site
• Induction of the blood coagulation
cascade
Coagulation Cascade

• Fibrinogen converts into fibrin


• Fibrin aggregate at injury site, causing
thrombus (clot) formation
• seals off damages area to prevent further
blood loss
• Process: 12+ blood clotting factors involved
in cascade
Coagulation Cascade
Coagulation pathway
Coagulation Factors
Coagulation Factors cont’d

• Roman numeral designation

• Intrinsic and extrinsic pathways

• Intrinsic - cascade that utilizes only


factors that are soluble in the plasma

• Extrinsic - some factors that are


insoluble in the plasma, e.g., membrane-
bound factors (factor VII)
Overview of blood coagulation
Release of ATP, factor V, fibrinogen, HMWK , Ca2+
Release of Prostaglandins
Vasocon-
striction
Adhesion to vWF Platelet Platelet
Activation Plug

Vessel Platelet
Aggregation Clot
Injury Thrombin
Tissue
Factor
Coagulation
Cascade

RJ Gillies
BC801

www.biochem.arizona.edu
Genetic disorders

• Lack of gene expression of clotting factor

• Altered amino acid sequence of clotting


factor

• Both intrinsic and extrinsic pathways


must work for proper clotting

• Results of mutations bruising or


prolonged bleeding
Disorders cont’d

• 90% of characterized disorders deficiency in


factor VIII, rest due to factor IX

• Treatment administration of whole blood or


relevant coagulation factor (purified from
whole blood)

• Recombinant factors important to minimize


risk of exposure to blood pathogens
Factor VIII - Hemophilia

Hemophilia A

• X-linked recessive disease

• Intact VIII- made up of 2 products, factor VIII


and von Willebrand factor (vWF)

• 1-2 million Da

• Fully intact VIII needed to enhance activation


rate of factor IX of intrinsic system
Factor IX

Hemophilia B

• Rarer disease

• Treatment is administration of
concentrated factor IX

• Produced recombinant in CHO cells

• Also X-linked recessive


How boys are affected ?
How girls may be affected ?
Symptoms of Hemophilia A

•Bruising •Prolonged
bleeding

•Spontaneous bleeding •Blood in the


urine or stool

•Bleeding into joints •Gastrointestinal tract


with pain and swelling and urinary tract
hemorrhage
Treatment

Without the use of blood donors


Production of factor VIII
• Native factor VIII is traditionally purified from blood
donations first screened for evidence of the presence of
viruses such as hepatitis B and HIV.
• A variety of fractionation procedures (initially mainly
precipitation procedures) have been used to produce a
factor VIII product.
• The final product is filter sterilized and filled into its
finished product containers.
• The product is then freeze-dried and the containers are
subsequently sealed under vacuum, or are flushed with an
inert gas (e.g. N2) before sealing.
• No preservative is added.
Anticoagulants

• Inappropriate clotting dangerous

• Occurs in blood vessels, impedes


blood flow

• Results in heart attack (coronary


thrombosis resulting in m.i.) or stroke
(blood vessel that supplies the brain)
Major Anticoagulants

• Heparin

• Warfarin

• Hirudin

• Ancrod

• Protein C

• Dicoumerol
Enzymes

• Streptokinase: Streptokinase is extracellular bacterial


protein produced by several strains of Streptococcus
haemolyticus group C.

• Urokinase: Urokinase is a serine protease produced by the


kidney and is found in both the plasma and urine

• Staphylokinase: Staphylokinase is a protein produced by a


number of strains of S. aureus that also displays therapeutic potential
as a thrombolytic agent.

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