Blood clotting Flashcards
Hemostasis
Blood clotting forming a thrombus at a site of vessel injury
Primary hemostasis: weak platelet plug, Interactions between platelets and vessel wall
Secondary hemostasis: strengthening the plug, by making a proteinatious clot (by fibrin) through the coagulation cascade of clotting factors
Primary hemostasis
Activated by disruption of endothelial cells (vessel damage)
vWF-von Willebrand Factor is released from endothelial cells (ECs) and platelet alpha granules(factor 4, fibrinogen, thrombospondin, fribronectin, PDGF, etc)
VWF unfolds under shear stress, opening the binding site for subendothelial collagen and Gp1B
Unfolding also exposes the cleavage sites for ADAMTS13: which prevents pathologic clotting–> thrombotic thrombocytopenic purpura (TTP)
Platelet tethering- platelets bind to vWF via GP1B
Binding (Platelet) to vWF (subendothelium) activates platelets causing them to change shape (morphology) and bind fibrinogen
Firm adhesion: integrin a2B1 on platelets bind to collagen for adhesion
after activation platelets aggregate and release their granules, the aggregation causes occlusive thrombus depends on a2bB3 (platelet assay tests activation adhesion and secretion)
Platelet Agonists
Secreted from activated platelets (act as amplifiers positive feedback), generated from blood or blood vessels (act as GPCRs)
Thromboxane A2 , ADP and Serotonin are secreted from activated platelets
Thrombin, Epinephrine, and collagen are secreted from blood and injury
platelet activation
Main effects: results in shape change in platelets (spiny sphere), and secretion of granules (ADP, serotonin, and TXA2
ADP induces platelets to express more integrin a2BB3
integrin a2bB3 activation: fibrinogen binds and crosslinks platelets making the plug bigger
(thromboxane A2)
TXA2 promotes platelet aggregation and vasoconstricts
Platelet plug is the end of primary hemostasis
Primary Hemostasis Disorders and tests
Seen as mucosal and skin bleeding, platelet quantity or quality
Dysfunction of molecules that interact with vWF
Bleeding time: measure of primary hemostasis (platelet) function because even if there are problems with secondary, the weak plug can stop bleeding
Invitro assays: test platelt aggregation, a2bb3-fibrinogen binding and secretion (take a blood sample, add agonists, stir measure clotting activity)
Secondary hemostasis
Blood coagulation system, making the fribrin clot (glue that seals the leak
Fibrin is an insoluble protein polymer that reinforces the primary hemostatic plug
Fibrin (dimer of 2 trimers, made in the liver and circulates in high concentrations)
Fibrinogen (1) can be made into fibrin by serine protease Thrombin (Factor 2 A) and vitamin K
Thrombin circulates as prothrombin (dysregulation of this causes problems)
Proteolytic cascades allow rapid generation of active thrombin from inactive prothrombin when needed (enzymes that activate the Coags are mostly Vitamin K dependent, and are localized on phospholipid surfaces, they have cofactors and have inhibitors)
Vitamin K
Essential Fat vitamin thats essential for synthesis of many coagulation factors (y carboxylase) create gla residues that associate with Calcium and phospho lipids
Vitamin K is recycled by VKORK (inhibited by warfarin)
Coagulation steps
- initiation (Intrinsic vs extrinsic, varies depending on path)
- amplification (thrombin mediates activation of more thrombin)
- stabilization (transglutaminase enzyme 13a cross links fibrin)
- termination (inhibition of coagulation of enzymes or destruction of cofactors)
- removal (fibrinolysis-> plasmin mediated degradation of clot
Initiation
extrinsic pathway (not found in blood): Tissue factor (found on all cells except ECs and blood cells) meets factor 7A (a vitamin K dependent serine protease), 7A activates 10
Intrinsic pathway (found in blood) Activated by tissue damage factors (platelts subendothelial collagen)
7-> 11 -> 9
