In people acclimated to high altitudes, the concentration of 2,3-diphosphoglycerate
(2,3-DPG) in the blood is increased, which allows these individuals to deliver a
larger amount of oxygen to tissues under conditions of lower oxygen tension.
Initially given high dose O2 through mask
Electron transport
Because there are many more oxygen molecules present in a given volume when
under pressure, hyperbaric oxygen dissolves in the blood in far greater amounts
enabling it to be transported to the cells. Hyperbaric oxygen (HBO) also helps rid
haemoglobin of the tenacious CO molecules, freeing it up for normal use once
more. The actual amount of oxygen molecules at a pressure of 3ata (20msw) in a
fixed volume is equal to 3 times the amount at the surface.
In cases of carbon monoxide poisoning, it normally takes over four hours for the
amount of CO in the body to fall by one half, during which time the tissues are
hypoxic due to replacement of O2Hb with COHb. Hyperbaric oxygen at 3ata
reduces this to 20 minutes, during which time the extra oxygen dissolved in the
blood alleviates hypoxia.
Prostaglandins
act in a manner similar to that of hormones, by stimulating
target cells into action.
differ from hormones in that they act locally, near their site
of synthesis, and they are metabolized very rapidly
the same prostaglandins act differently in different tissues
Hemostasis & Thrombosis: Hemophilia
Beth A. Bouchard
BIOC 212: Biochemistry of Human Disease
Spring 2005
HEMOSTASIS
1). INITIATION
Vessel wall – endothelial cells and subendothelial components
2). LOCALIZATION
Platelets – circulating cellular elements
3). PROPAGATION/AMPLIFICATION
Plasma coagulation proteins (factors)
4). TERMINATION
Plasma coagulation protein inhibitors
5). ELIMINATION
Fibrinolytic system
BLOOD COAGULATION
BLOOD COAGULATION (CONT.)
• Deficiencies in all of the factors, except factor
XII, lead to a bleeding tendency in the affected
individual
• Described as a ‘waterfall’ or ‘cascade’ sequence of
zymogen (pro-enzyme) to enzyme conversions, with
each enzyme activating the next zymogen in the
seqeunce
• Activated factor enzymes are designated with an
“a”, e.g. factor Xa
Common constituents of coagulation
complexes
Vitamin K-dependent (VKD) zymogen
Ca2+
Protein cofactor
Appropriate membrane surface
- activated platelets (VIIIa/IXa complex, Va/Xa complex)
- subendothelial cells, typically fibroblasts (TF/VIIa complex)
Common constituents of coagulation
complexes
Vitamin K-dependent (VKD) zymogen
Ca2+
Protein cofactor
Appropriate membrane surface
- activated platelets (VIIIa/IXa complex, Va/Xa complex)
- subendothelial cells, typically fibroblasts (TF/VIIa complex)
Functional Domains of the Vitamin Kdependent Zymogens
Gamma (g)-carboxyglutamic acid
VITAMIN K
• Group of related, fat soluble compounds, which
differ in the number of side-chain isoprenoid units
• Plant derived (vitamin K1) and synthesized by
intestinal bacteria (vitamin K2)
• The reduced form of vitamin K2 (vitamin KH2) is
required for the post-translational, gammacarboxylation of several proteins involved in blood
clotting
Formation of Gla residues subsequent to
protein synthesis (post-translational)
Vitamin K deficiency
• Deficiency of vitamin K is rare because of its wide
distribution in nature, and its production by intestinal
bacteria
• Found in individuals with liver disease and fat malabsorption
- it is associated with bleeding disorders
• Newborn infants (especially preemies) are also at risk
- Placenta is insufficient in the transfer of maternal vitamin K
- Concentration of circulating vitamin K drops immediately after
birth, and it recovers upon absorption of food
- Gut of the newborn is sterile
Thus, newborns are given an injection of vitamin K following
birth.
Common constituents of coagulation
complexes
Vitamin K-dependent (VKD) zymogen
Ca2+
Protein cofactor
Appropriate membrane surface
- activated platelets (VIIIa/IXa complex, Va/Xa complex)
- subendothelial cells, typically fibroblasts (TF/VIIa complex)
Prothrombin
-Thrombin
Prothrombinase
Components
FXa
Ca2+FXa
2+
FVa Ca
HC
Ca2+ FXa
FVa HC 2+
Ca
FVa LC
Relative Rate
of Prothrombin
Activation
1
300,000
FVa LC
Ca2+ FXa
Ca2+
30
Prothrombinase
Ca2+ FXa
FVa HC
FVa LC
Relevance of complex formation and its constituents
300
Common constituents of coagulation
complexes
Vitamin K-dependent (VKD) zymogen
Ca2+
Protein cofactor
Appropriate membrane surface
- activated platelets (VIIIa/IXa complex, Va/Xa complex)
- subendothelial cells, typically fibroblasts (TF/VIIa complex)
** Express anionic phospholipids and membrane receptors
for coagulation proteins.
In platelets, the expression of this membrane surface is activation-dependent.
Extrinsic Tenase
Intrinsic Tenase
Ca2+
TF FVIIa
Ca2+
FIXa
Ca2+
Ca2+FIXa
FVIIIa
Thrombin
Cleaves Fibrinogen
Activates Platelets
Activates procofactors
(FV and FVIII)
Activates zymogens
(FVII, FXI and FXIII)
FXa
Ca2+
FXa
2+
FVa Ca
HC
FVa LC
Prothrombinase
IIa
Intrinsic Pathway of Blood Coagulation
• No factors extrinsic to the blood are involved
• Clinical test to assess the functionality of this
pathway is the activated partial thromboplastin
time (aPTT)
– Kaolin and cephalin are added to the test plasma sample
– The normal range is ~30 – 50 seconds (varies slightly
depending on the laboratory)
– Prolongations in the aPTT are observed in deficiencies of
factors XI, IX, VIII, X, and V, prothrombin, or
fibrinogen.
– Used to test for common congenital hemophilias
(deficiencies in IX, VIII, or XI) and to monitor heparin
treatment
Extrinsic Pathway of Blood Coagulation
• Extrinsic refers to tissue factor, which is
expressed on subendothelial cells
• Clinical test to assess the functionality of this
pathway is the prothrombin time (PT)
– Lipidated tissue factor is added to test plasma sample
– The normal range is ~10-15 seconds (varies slightly
depending on the laboratory)
– Prolongations in the PT are observed in deficiencies of
factors VII, X, V, prothrombin, or fibrinogen.
– Used to test for the rare congenital deficiencies in these
factors: More often it is used to diagnose acquired
bleeding disorders resulting from vitamin K deficiency,
oral anticoagulants (e.g. warfarin), and liver disease
Thrombin Time (TT)
In this test, thrombin is added to plasma
– The normal range is ~10-15 seconds (varies
slightly depending on the laboratory)
– Prolongations in the TT are observed in
congenital fibrinogen deficiency or acquired
fibrinogen deficiency resulting from
consumption of fibrinogen in DIC (disseminated
intravascular coagulation), or may occur
following treatment with fibrinolytic drugs
Hemophilias A and B
• Hemophilias A and B are cause by deficiencies in
factors VIII or IX, respectively
• Affect ~1 in 10,000 males
• Inherited as a recessive X-linked trait (Mom would
be an unaffected carrier)
• Treated by administration of factor VIII or
factor IX concentrates
• Recombinant factor VIII or XI
• Gene therapy trials
HEMOSTASIS (CONT.)
1). INITIATION
Vessel wall – endothelial cells and subendothelial components
2). LOCALIZATION
Platelets – circulating cellular elements
3). PROPAGATION/AMPLIFICATION
Plasma coagulation proteins (factors)
4). TERMINATION
Plasma coagulation protein inhibitors
5). ELIMINATION
Fibrinolytic system
INHIBITORS
INHIBITORS (cont.)
FIBRINOLYSIS
FIBRINOLYSIS (CONT.)
Bleeding disorders can span the spectrum from weeping
blood vessels to full-fledged internal and external
hemorrhage
Hemorrhage
Genetic defects:
platelet abnormalities
blood vessel wall abnormalities
clotting factor deficiencies (hemophilias)
excess clot breakdown (fibrinolysis)
Acquired defects:
liver disease (site of clotting factor synthesis)
vitamin K deficiency
autoimmune disease (platelet destruction)
trauma
Bleeding disorders can span the spectrum from weeping
blood vessels to full-fledged internal and external
hemorrhage
Hemorrhage
Treated by factor replacement
Thrombosis can be manifested as a transient, short-term
or episodic event in individuals with chronic or recurring
clotting. It is the major cause of both stroke and heart
attacks.
Thrombosis
Genetic defects:
clotting factor INHIBITOR deficiencies
decreased fibrinolysis
Acquired defects:
atherosclerosis
Antithrombotic Attributes of Vascular
Endothelium
Pharmacologic Approaches to Prevent
Thrombosis
Antiplatelet agents - block activation,
aggregation or intraplatelet agonist synthesis
Effective anticoagulant therapy includes both
antiplatelet and antithrombin agents
Blood “thinners” - coumadin (warfarin): inhibition of “gla” formation
in the liver
Coumadin blocks reformation of reduced vitamin K, which essentially
stops the post-translational modification of the glutamic acid residues
at the amino-termini of the VKDP’s, since vitamin K is oxidized during
the reaction.
Blood “thinners” - heparin: potent cofactor for ATIII-catalyzed
inhibition of procoagulant serine proteases
Snakes
Leeches
Blood-sucking Insects