Overview Of Hemostasis (Schalm 87) Flashcards
(51 cards)
What are the two components of coagulation complexes? At what site are they normally bound and act?
Cofactors and Enzymes
They bind and act at a procoagulant membrane surface
How are coagulation enzymes inhibited (4 mechanisms)?
Enzyme cleavage
Active site blockade
Stable complex formation
Substrate modification
How does membrane binding enhance coagulation enzyme activity?
Membrane binding properly aligns the participating proteins
How do coagulation factors VII, IX, X, prothrombin, and proteins C, S, and Z bind to a membrane surface?
They contain gammacarboxyglutamic acid (GLA) residues that interact with calcium and negatively charged phospholipids
What is required for carboxylation of glutamic acid precursors to GLA domains?
The vitamin K cycle in the liver
What complex formation characterizes the extrinsic coagulation pathway?
Tissue factor and activated factor VII (TF-FVIIa) - > generates activated factor X
What complex formation characterizes the intrinsic coagulation pathway?
FXIa-FVIIIa -> ultimately results in FXa generation
What complex formation characterizes the common pathway?
FXa-FVa -> activates prothrombin to generate thrombin, which cleaves fibrinogen to fibrin
Which coagulation cofactors have regions that interact with phospholipids, allowing fully functional enzymatic complexes to assemble on a membrane surface?
Factors V and VIII
What two zygomogens and single cofactor make up the contact pathway?
Factor XII and prekallikrein (zymogens)
High-molecular-weight Kininogen (HK)
When does contact activation of coagulation occur?
When FXII, PK, and HMW spontaneously assemble on a suitable negatively charged surface - this occurs when blood is removed from the vascular system and comes into contact with an artificial surface (resulting in the “intrinsic” clotting potential of blood)
How is the contact pathway of coagulation affected by calcium chelators (citrate, EDTA)?
It is not affected as it is not calcium dependent (and may influence viscoelastic tests that utilize a holding period);
Seems most pronounced in equine, then canine, then human samples
What role does the contact pathway play during normal in vivo coagulation?
Little to none;
It may play a role in pathological thrombus formation, potentially binding to RNA, polyphosphate (e.g. ADP, ATP), or misfolded proteins
What physiologic roles does the contact pathway play?
Bradykinin generation (after activation on negatively charged phospholipid membranes)
Angiogenesis
Profibronlyitic, proinflammatory, and anti-adhesive properties
What mineral is required for HK binding to membranes surfaces?
Zinc
Name three functions of kinongens?
Inhibition of atrial natriuretic peptide
Prevent calpain-mediated platelet aggregation
Prevent thrombin binding to platelets
Release bradykinin (after cleavage by kallikrein) - a vasoactive peptide
What are two cell types that express abundant tissue factor (FIII)?
Adventitial cells surrounding blood vessels larger than capillaries
Differentiating skin keratinocytes/other epithelial cells
(This distribution is consistent with TF’s function as a protective “hemostatic envelope”)
What is the likely source of blood-borne tissue factor?
Monocytes or microvesicles from TF-bearing monocytes
What outer membrane phospholipid may play a role in maintaining TF in an encrypted state?
Sphingomyelin
Which coagulation factor zymogen has the shortest half-life?
Factor VII - thus it’s levels decrease rapidly if liver function or vitamin-K cycle is impaired
The activated form of Factor VII (FVIIa) has the LONGEST half-life of the enzymes, approximately 2 hours (others are measured in seconds)
How does the presence of circulating FVIIa affect hemostasis?
Exposure of blood to TF allows formation of both TF-FVIIa and TF-FVII complexes. THe TF-FVIIa complexes probably generate sufficient enzymatic activity to trigger the clotting cascade
What are the main inhibitors of the TF-FVIIa complex?
Tissue factor pathway inhibitor (TFPI) - FXa complex
Heparin - antithrombin
Where does the intrinsic cascade primarily occur?
It primarily occurs on the surface of activated platelets, which expose binding sites for FIXa, FVIIIa, and FX, greatly increasing the rate of FXa generation by many millionfold
What is the primary binding site for FXI? What is the preferred substrate for FXIa?
The GPIb-alpha subunit of the GPIb/IX/V complex
The preferred substrate is FIX (will also cleave additional FXI)
