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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. BouchardBIOC 212: Biochemistry of Human Disease
Spring 2005
HEMOSTASIS
1). INITIATIONVessel wall – endothelial cells and subendothelial
components
2). LOCALIZATIONPlatelets – circulating cellular elements
3). PROPAGATION/AMPLIFICATIONPlasma coagulation proteins (factors)
4). TERMINATIONPlasma coagulation protein inhibitors
5). ELIMINATIONFibrinolytic 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+
Appropriate membrane surface
- activated platelets (VIIIa/IXa complex, Va/Xa complex)
- subendothelial cells, typically fibroblasts (TF/VIIa complex)
Protein cofactor
Common constituents of coagulation complexes
Vitamin K-dependent (VKD) zymogen
Ca2+
Appropriate membrane surface
- activated platelets (VIIIa/IXa complex, Va/Xa complex)
- subendothelial cells, typically fibroblasts (TF/VIIa complex)
Protein cofactor
Functional Domains of the Vitamin K-dependent Zymogens
Gamma ()-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, gamma-carboxylation 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
Protein cofactor
Ca2+
Appropriate membrane surface
- activated platelets (VIIIa/IXa complex, Va/Xa complex)
- subendothelial cells, typically fibroblasts (TF/VIIa complex)
Ca2+
FXaCa2+ 30
Ca2+
FXa
FVa HC
FVa LC
Ca2+
300,000
-Thrombin
ProthrombinaseComponents
Relative Rateof Prothrombin
Activation
FXa 1Prothrombin
Ca2+
FXa
Prothrombinase
FVa HC
FVa LC
Ca2+
FXa 300FVa HC
FVa LC
Ca2+
Relevance of complex formation and its constituents
Common constituents of coagulation complexes
Vitamin K-dependent (VKD) zymogen
Protein cofactor
Ca2+
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.
Ca2+FVIIaTF
Extrinsic TenaseCa2+
Prothrombinase
Ca2+
FXa
FVa HC
FVa LC
Ca2+
Ca2+FIXaFVIIIaCa2+
Intrinsic Tenase
FXa
FIXa
IIa
ThrombinCleaves Fibrinogen
Activates Platelets
Activates procofactors (FV and FVIII)
Activates zymogens (FVII, FXI and FXIII)
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). INITIATIONVessel wall – endothelial cells and subendothelial
components
2). LOCALIZATIONPlatelets – circulating cellular elements
3). PROPAGATION/AMPLIFICATIONPlasma coagulation proteins (factors)
4). TERMINATIONPlasma coagulation protein inhibitors
5). ELIMINATIONFibrinolytic system
INHIBITORS
INHIBITORS (cont.)
FIBRINOLYSIS
FIBRINOLYSIS (CONT.)
Hemorrhage
Bleeding disorders can span the spectrum from weeping blood vessels to full-fledged internal and external hemorrhage
Genetic defects:platelet abnormalitiesblood vessel wall abnormalitiesclotting factor deficiencies (hemophilias)excess clot breakdown (fibrinolysis)
Acquired defects:liver disease (site of clotting factor synthesis)vitamin K deficiencyautoimmune disease (platelet destruction)trauma
Hemorrhage
Bleeding disorders can span the spectrum from weeping blood vessels to full-fledged internal and external hemorrhage
Treated by factor replacement
Thrombosis
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.
Genetic defects:clotting factor INHIBITOR deficienciesdecreased 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-catalyzedinhibition of procoagulant serine proteases
Snakes
Leeches
Blood-sucking Insects