Exam 3- Groseclose Flashcards
Where does factor X occur in the coagulation scheme? What does it do?
Factor X occurs in the common pathway. In the active form, it catalyzes the conversion of Prothrombin into Thrombin
What is the importance of vitamin K to the coagulation cascade?
Many clotting factors are vitamin-K dependent (Factors II, VII, IX, and X, plus Protein C and Protein S)
Does vitamin K participate directly at the site of clotting?
No, at the liver
What is the role of gamma-carboxyglutamate residues in clotting factors?
The addition of gamma-carboxyglutamate residues to certain clotting factors (II, VII, IX, and X) makes each a divalent anion, which can then bind a calcium ion. It is the Ca-complexed portion of the clotting factors that interact with phospholipids which provide an attachment site for clotting factors
Many activated coagulation factors are enzymes. What class of reactions do they catalyze?
They are almost all protease … they cleave proteins by hydrolysis in order to activate them
What is “antihemophilic factor”, and at what stage does it function?
Factor VIII is “antihemophilic factor”. It is not an enzyme, but a protein cofactor. It circulates with vWF and acts to convert Factor X to Factor Xa
Name the K dependent factors
Factors II, VII, IX, and X plus Protein C and S
How does Factor XIIIa differ from the other enzymes of the coagulation cascade?
Factor XIIIa is Fibrin Stabilizing Factor (FSF). It is an enzyme that cross-links fibrin strands to form a stable 3D clotting network. It is activated by thrombin, and is the only non-protease enzyme in the cascade. (It is a transamidase)
Which 2 proteins of the cascade are not enzymes?
Factor VIII is not an enzyme, it is a protein cofactor
Factor V is not an enzyme, it is a protein cofactor
At which amino acid does K-dependent carboxylation occur?
It occurs at the n-terminus glutamate residues on the vitamin-K dependent clotting factors
Where are the components of the cascade synthesized?
The plasma-borne clotting factors are synthesized in the liver. Factor XIII and vWF are made by megakaryocytes and renal tissue.
Discuss the ways in which coagulation is regulated.
Blood flow dilution of components
Liver uptake and inactivation of activated factors
Endogenous inhibitors of the coagulation process
Undamaged endothelial cells generate anti-aggregants
Activated factors break down others
Discuss the merits and drawbacks of anticoagulant therapy with heparin versus vitamin K antagonists.
Heparin enhances the action of antithrombin III, which binds to the active site of thrombin (and Xa and IXa) to inactive them. This action is extremely rapid and significant. The disadvantage is that it may cause unwanted bleeding. Patient without antithrombin III, won’t work.
Vitamin K antagonists suppress the post-translational carboxylation of vitamin-K dependent factors. This action is considerably slower, as it can only act as fast as the fastest forming clotting factor (VII). This is a better choice for long-term clotting control since it acts more slowly and more moderately.
- The disadvantage is that vitamin K antagonists can lead to atherosclerosis. MGP (matrix gla protein) and Gas-6 (growth arrest specific gene 6) are also under vitamin K control. MGP inhibits calcification, Gas-6 induces cell survival and movement. Without vitamin K, apoptosis, calcification, and immobility ensue —> atherosclerosis
Describe the mode of action of heparin
Heparin enhances the action of antithrombin III, which binds to the active site of thrombin (and Xa and IXa) to inactivate them
Discuss the advantages and disadvantages of the therapeutic use of
(1) streptokinase
(2) tissue plasminogen activator (TPA)
(3) urokinase
These 3 proteins are used as anticoagulants
Streptokinase:
Advantages: bacterial protein (not enzyme)
Disadvantages: can cause generalized bleeding, may invoke an immune response
TPA:
Advantages: more active toward plasminogen bound to fibrin
Disadvantages: brain bleeds?
Urokinase:
Advantages: ????
Disadvantages: can activate plasminogen floating in plasma, which leads to generalized bleeding
What is the structure of fibrinogen and how does it differ from that of fibrin?
Fibrinogen is a precursor to fibrin. It is a large glycoprotein of 6 subunits. It is very soluble due to presence of charged groups
To yield fibrin, the charged groups are cleaved, so fibrin is not soluble and precipitates as long, tangled threads of protein
How does protein C inhibit coagulation?
Protein C is a vitamin-K dependent proenzyme activated by thrombin to protein C. It’s activated form is a protease which breaks down factors Va and VIIIa
With which factor is vWF associated?
VIIIa
Name 3 processes (besides clotting) that are necessary for normal Hemostasis.
Vessel constriction
Platelet adhesion and activation
Fibrinolysis
Discuss the role of platelets in Hemostasis.
Platelets are anucleate fragments of cytoplasm pinched off from megakaryocytes. The activation of platelets causes the exposure of phospholipids on the plasma membrane, which provide an attachment point for activated clotting factors
Platelets also contain clotting factors V, VIII, and XIII
Which arachidonic acid metabolite is produced by platelets? Which is produced by endothelial cells?
Thromboxane A2 (powerfully pro-thrombotic factor- platelet aggregation and arterial constriction) - family of prostacyclin
Endothelial cells produce antiaggregant and vasodilator (Prostacyclin, PGI2)
What’s so special about alpha2-macroglobulin?
Inhibitor of coagulation and of fibrinolysis
Inhibits thrombin, plasmin and kallikrein
—> 1 of the endogenous inhibitor of coagulation
Give another name for heme. What is the word that means “heme containing protein”?
Iron = protoporphyrin IX Cytochromes = heme containing proteins
Name at least three proteins that contain heme.
Hemoglobin
Myoglobin
Enzymes: catalase, peroxidases, tryptophan oxygenate
Cytochromes: P450 (CYP450), Cyt c, cyt b5
