Hemostasis - Coagulation/Fibrinolysis Flashcards
hemostasis
prevention of hemorrhage following vascular injury
primary hemostasis
vasoconstriction and platelet plug formation
secondary hemostasis
fibrin formation
activation of coagulation
a. Vessel injury: exposure of subendothelial collagen. Collagen activates FXII and also binds glycoprotein VI, activating platelets. Activated platelets contribute to thrombin generation; this does not require FXII, explaining lack of bleeding with XII deficiency.
b. Endothelium releases endothelin, a vasoconstrictor, as well as P-selectin and von Willebrand factor from Weibel-Palade bodies (organelles in endothelial cells)
c. von Willebrand factor is necessary for platelet adherence to the subendothelium in high-shear vessels such as arteries and arterioles. It binds to collagen and platelet glycoprotein 1b, and is degraded by ADAMTS13.
d. P-selectin promotes rolling of leukocytes and platelets on activated endothelium
e. Blebs form on leukocytes and are shed as microparticles bearing tissue factor; these dock and fuse with activated platelets
f. In addition, glycoprotein Ib-V-IX on platelet surface binds vWF/FVIII, FXI, & thrombin, glycoprotein IIb/IIIa binds prothrombin and fibrinogen, and FV and fibrinogen are released from platelet α-granules.
describe the coagulation cascade
at each step of the cascade, an enzyme cleaves (by proteolysis) the next factor, activating it. The cleaved factor (a zymogen) becomes an enzyme (or cofactor for an enzyme) and works on the next step of the process
Prothrombin Time (PT)
addition of a high concentration of tissue factor results in formation of TF-VIIa complex which activates FX; FXa with FV & calcium, converts prothrombin to thrombin, & thrombin converts fibrinogen to fibrin (insoluble clot). Note that the clotting time becomes truly prolonged when the concentration of one or more clotting factors (FV, VII, X, prothrombin) is less than 30% of normal
Activated Partial Thromboplastin Time (aPTT)
addition of a silicate activates FXII; provision of phospholipid & calcium accelerates the clotting time. As with the PT, the aPTT becomes clearly prolonged when the concentration of any of the clotting factors, except FVII, is less than 30% of normal
FXII, FXI, PreKallikrein, & High Molecular Weight Kininogen
discovered because patients deficient in these factors had a prolonged aPTT. However, only FXI deficiency is associated with a mild/moderate bleeding disorder. FXII, Prekallikrein,& HMWKininogen involved in complement cascade and bradykinin formation. FXI binds to activated platelets, is activated by thrombin, and catalyzes the conversion of FIX to FIXa (but tissue factor-FVIIa complex also does this)
factors involved in initiation of coagulation
Tissue factor and FVII
factors involved in coagulation amplification
factors V, VIII, and XI
factors involved in coagulation propagation
factor X and prothrombin
Vitamin K and coagulation
Vitamin K is the coenzyme for the carboxylase that attaches carboxyl groups to glutamic acid residues of clotting factors II,VII, IX, X and inhibitors proteins C, S, and Z. These negatively charged groups enable the clotting or inhibitor proteins to form Ca2+ bridges with negatively charged membrane phospholipids, an essential step for their activity. During the carboxylase reaction, vitamin K is oxidized but returned to its reduced form by the liver enzyme, VKORC1
thrombin
binds to and cleaves Protease Activated Receptor 1 (PAR1) on the platelet surface; PAR1 promotes platelet degranulation, changes in phospholipid composition, and activation of glycoprotein IIb/IIIa. Thrombin releases FVIII from von Willebrand factor and activates it, FV, FXI, & FXIII. In the absence of FVIII or FIX (hemophilia), FVIIa, FXa and thrombin are rapidly inactivated by tissue factor pathway inhibitor & antithrombin (see below), and fibrin formation is greatly attenuated
fibrinogen
dimer of 3 interwoven peptide chains. When 2 small fibrinopeptides are cleaved from the Aα & Bß-chains by thrombin, the dimers aggregate by forming non-covalent bonds between terminal D-domains on one molecule and the central E-domain of a second molecule giving a pattern that looks like a bricks in a wall. Thrombin-activated FXIII then catalyzes bond formation between glutamic acid of one D-domain and lysine of an adjacent D-domain. This accounts for the incredible strength of the fibrin strand
antithrombotic agents
nitric oxide, prostacyclin, and ecto-ADPase
tissue factor pathway inhibitor (TFPI)
thrombomodulin
proteoglycans
ADAMTS13
tissue factor pathway inhibitor (TFPI)
blocks the FVIIa-tissue factor complex
thrombomodulin
binds thrombin and activates protein C
proteoglycans
activate antithrombin
ADAMTS13
is present on the endothelial cell membrane and cleaves the highest molecular weight multimers of von Willebrand factor as they are released by the Weibel-Palade bodies
antithrombin
a serine protease inhibitor (serpin) that blocks thrombin and activated factors X, IX, XI, XII, and the tissue factor-VIIa complex
proteins C and S
synthesized in the liver and have homology with factors II, VII, IX, and X
protein C activated by thrombin-thrombomodulin
activated protein C inactivates clotting factors Va and VIIa, protein S is the cofactor
protien S circulates free (1/3) and bound (2/3) to the C4B-binding protein (C4BP)
only free fraction is cofactor for protine C
protein Z
binds to Z protease inhibitor and the complex inhibits factor Xa
phospholipid-binding proteins
annexin V and beta2-glycoprotein-1, bind to phosphatidyl serine, preventing binding of the coagulation complexes
fibrinolytic system
consists of plasminogen, which forms plasmin, the enzyme that lyses fibrin clots.
Tissue plasminogen activator (t-PA) and urokinase convert plasminogen to plasmin, but this process is most effective when plasminogen is bound to lysine-binding sites on fibrin.
inhibitors of the fibrinolytic system
Plasminogen activator inhibitor-1 (PAI-1), lipoprotein(a), and thrombin activatable fibrinolysis inhibitor (TAFI) either bind to or degrade lysine binding sites on fibrin and thereby inhibit fibrinolysis. Epsilon aminocaproic acid and tranexamic acid are pharmacologic lysine-mimetics. Antiplasmin directly inhibits plasmin
