Hemostasis Flashcards
What is hemostasis? What are the two outcomes of an out of balance hemostatic system?
prevention of blood loss upon injury to the vessel and reestablishment of blood flow; hemorrhage and thrombosis
What 5 things cause a thrombosis?
blood flow or hemodynamics, blood vessel wall, blood constituents, genetic, and aquired
What 4 things can cause a hemorrhage?
synthesis or function of clotting and anti clotting factors, generation and function of platelets, genetic diseases, acquired
What are the three functional attributes of the hemostatic system?
self-aware and everywhere, self sustaining, autoregulation
What is a thrombus?
abnormal clot that develops in a blood vessel
What is an embolus?
a clot that flows freely in the blood
What is an infarct?
necrotic tissue area formed due to obstruction of blood due to an embolus or a thrombus
What are the components of the hemostatic system?
platelets, plasma, blood vessel constituents: endothelial cells, basement membrane, smooth muscle cells and fibroblasts, Tissue/cells where clotting are synthesized and degraded
what triggers and what are the steps of the hemostatic cascade?
injury or pathology disturbs endothelial cells, basement membrane components are exposed; vasoconstriction, platelet adhesion and aggregation, coagulation, blood vessel repair, and clot dissolution
Describe the set up of the vessel wall inside to out.
smooth surface endothelial cells, basement membrane, ECM containing fibroblasts, and smooth muscle cells surrounding
What is the first stage of platelet activation and plug formation?
initiation and activation, adhesion of platelets to thrombogenic substrates or injured vessel wall components, this activates platelets and induces shape changes and signaling cascades
What is the second stage of platelet activation and plug formation?
extension: release of calcium, ADP, TXA2, thrombin, this recruits additional platelets to the site of injury
What is the third stage of platelet activation and plug formation?
perpetuation: events that stabilize platelet to platelet adhesion resulting in formation of the platelet plug
Name the adhesion receptors on platelets and what they interact with.
GP-VI binds with collagen, GP1b-IX-V binds with vWF, GPIb/IIa (alpha 2/ beta 1) mediates binding with collagen, GP IIb/IIIa (alpha IIb/ beta III) mediates adhesion between platelets via fibrinogen, GPCR Gs binds with PGI2, GPCR Gq binds with TXA2, uPAR Gq binds with Thrombin, P2Y1 Gi and P2Y2 Gq binds with ADP, GPCR PAR 1 and PAR 2 both bind to thrombin
What happens when GP-VI binds to exposed collagen?
initiates a signaling cascade to activate platelets
What happens when vWF binds to GP1b-IX-V?
after undergoing a change vWF has an increased affinity for GP1b-IX-V, upon forming the GP1b-IX-V-vWF complex binds to collagen which initiates platelet adhesion to the exposed vessel surface
What else does vWF do besides bind GP1b-IX-V?
some remains bound to the basement membrane, vWF transports and sequesters coagulation factor VIII
What does integrin alpha 2 beta 1?
mediates adhesion of platelets to collagen on the exposed vessel surface
What does integrin alpha IIb beta 3?
mediates adhesion between platelets via fibrinogen
Where is vWF made and stored?
synthesized by endothelial cells and megakaryocytes and are stored in the platelets and endothelial cells
Which receptors and their substrates activate platelets in the coagulation cascade?
ADP activates via receptors P2Y1(Gi) and P2Y2(Gq), thrombin a protease binding with PAR1 and PAR2, and TXA2 which is coupled with Gq or Gi
Which receptors and their substrates inhibit platelet coagulation?
PGI2 and is coupled to Gs
Describe the steps of initiation of the clotting cascade.
hemodynamic changes induce a conformational change in GP1b-IX-V increasing its affinity for vWF, their binding triggers a signaling cascade, this permits the initial adhesion of rolling platelets to collagen via vWF, adhesion of platelets to collagen is strengthened and stabilized thru alpha2beta1 and GP-VI, this activates platelets and initiates a shape change and forces them to exocytose stored TXA2, ADP and thrombin
Describe the extension and perpetuation of the platelet plug formation.
TXA, ADP and thrombin are released by activated platelets on collagen bed, they bind to GPCRs on circulating platelets nearby activating them and recruiting them to the site of the injury where the new platelets adhere to the other platelets by crosslinking of alphaIIbeta3 via fibrinogen forming the hemostatic plug
Negatively charged phospholipids translocate to the outer membrane leaflet of platelets why?
allows the assembly of the tenase complex and the prothrombinase complex which assures platelet aggregation and activation as well as clotting cascade initiated and restricted to site of injury or are constrained locally
What do pro-coagulation factors do?
activated temporarily upon injury or in disease states, end point is to produce thrombin which coagulates blood via changing fibrin into fibrinogen
What do anti-coagulation factors do?
prevent clotting and/or dissolve clots; most dedicated to inhibiting thrombin activity or destroy factors that facilitate the production of thrombin
What are the four categories or classes of clotting and anticlotting factors?
enzymes, cofactors, control proteins, and substrates
What are some common properties and examples of enzyme clotting and anticlotting factors?
circulate in inactive form (zymogens or proenzymes) bound to serpins, serine proteases, activated via proteolytic cleavage, contain 3 domains GLA 9undergoes gamma carboxylation, Kringle (regulatory), and the Catalytic domain; Prothrombin, Protein C, Prekallikrein, Factor VII, IX, X, XI, XII, & XIII
What are some common properties and examples of cofactor clotting and anticlotting factors?
bind and stabilize clotting factors but have no enzyme activity; Tissue factor, Thrombomodulin, Protein S, HMWK, Factor V and VIII