NBME - 6/16 - Blood plasma proteins, Coagulation, and Fibrinolysis Flashcards
Primary function of Albumin, which makes up 60% of total protein
Osmotic pressure maintenance brings water back out of tissues
Functions of Globulin (4), which make up 35% of total protein
Transport nutrients, vitamins, metals, hormones, metabolites
Defense against infection
Regulatory processes
Blood Clotting – hemostasis
What initiates coagulation?
Coagulation is initiated by TF binding to factor VIIa. The TF-VIIa complex activates small amounts of factors IX and X. Factor X associates with its cofactor Va forming a complex on the TF-bearing cell that converts prothrombin to thrombin. Active Xa is localized to the site of its activation.
Feedback processes going on during the initiation phase of Coagulation
Free Xa is inhibited in the circulation by antithrombin III (ATIII) and other serpins.
ATIII, the major inhibitor of thrombin, also inactivates most of the other coagulation proteases as well, including IXa, Xa and XIa, ensuring that fibrin clots are not formed in the circulation.
When does Amplification take place?
Amplification takes place only when damage to the vasculature allows platelets and factor VIII/vWF access to the TF-bearing cells at the site of injury.
What happens now that we have Thrombin floating around in the Amplification phase?
Platelets release additional factor V, and thrombin activates it forming more active Va/Xa complexes on the platelets. Hence thrombin levels are amplified.
Thrombin also releases VIIIa from the VIII/vWF complex. VIIIa then binds to activated platelets. Factor XI is also activated.
Where does Propagation occur?
Propagation occurs on the surface of large numbers of platelets at the site of injury.
Discuss the role of factors 9, 10, and 11 i nthe formation of the hemostatic plug
Factor 9a activated during the initiation phase binds to factor 8a on the platelet surface. Additional 9a is supplied by platelet-bound 11a.
Factor 10 from the plasma is activated to 10a at many sites on platelets, generating a burst of thrombin large enough to clot fibrinogen and form a hemostatic plug
Discuss how platelets adhere to the subendothelium
Adhesion of platelets to the subendothelial layers. (1) GPIa initially binds to exposed collagen, which results in conformational changes of the complex and cells round up. (2) Conformational changes allow GPIb to interact with vWF (3) The second binding event exposes the GPIIb/GPIIIa complex, which also binds to vWF and interacts with fibrinogen.
How are factor complex proteins bound to the plasma membrane?
Factor complex proteins contain γ-carboxyglutamate residues that bind to Ca2+ ions coordinated to phospholipid (PL) head groups on the plasma membrane, thereby anchoring the complexes to the cell surface.
What key ingredient is needed to form the γ-carboxyglutamate residues needed to anchor the factor complexes.
Vitamin K
For exorbitant uneeded detail see below.
How does Warfarin work?
Warfarin (Coumadin) is a slow and long-acting anticoagulant. It is an analog of vitamin K, that blocks the gammacarboxylation reaction (inhibits vitamin K epoxide reductase).
The non-carboxylated blood clotting proteins are unable to promote blood coagulation because they cannot bind calcium and thus cannot bind to their phospholipid sites of activation.
Endothelial cells have three anticoagulant functional abilities. What are they? No detail yet.
- Protein C–Protein S–Thrombomodulin system
- Antithrombin III (ATIII) and tissue factor pathway inhibitor (TFPI)
- Endothelial cells themselves inhibit platelet activation and aggregation
Discuss the Protein C–Protein S–Thrombomodulin system
Protein C–Protein S–Thrombomodulin system inactivates factor Va and VIIIa
Thrombin, bound to thrombomodulin on a healthy endothelial cell surface, activates protein C. Activated protein C, in complex with protein S, binds to the platelet membrane, and the activated protein C complex (APC) destroys Factors Va and VIIIa by proteolytic cleavage, thereby inhibiting the coagulation cascade.
Discuss Antithrombin III (ATIII) and tissue factor pathway inhibitor (TFPI)
Belong to the class of serpins (serine protease inhibitors) always present bound to heparan sulfates on the vascular endothelial cell surface (also present in the circulation).
ATIII inhibits thrombin, and most other factor serine proteases especially, IXa and Xa
TFPI inhibits TF-VIIa complex, also Xa.