Hemostasis and Coagulation Cascade Flashcards
Zymogen and Serine Protease
Zymogen, aka proenzyme – inactive enzyme precursor
Serine protease: an enzyme that cleaves peptide bonds
Serine is the nucleophilic amino acid in the enzyme’s active site
Cleavage of disulfide bonds causes activation
Extrinsic 10ase
TF (VIIa), factor 10 (inactive), Ca2+, and phosphotidylserine to cleave the factor 10 and make it active
Gamma - Carboxyglutamate (GLA)
aka Gla residue
Post-translational modification of glutamate
Found in Prothrombin, Factors VII, IX, and X, and proteins C, S and Z
Binds calcium ions:
Aids binding of coagulation cascade proteins to membrane components
Necessary for cleavage activity of the serine proteases
GLA = binds Ca2+ to allow molecules to bind to membrane surfaces
Factor 7 in extrinsic
9- intrinsic pathway
10 – cleaves thrombin
Proteins C, S, and Z – involved in anti-coagulations
Synthesis of GLA
Requires vitamin K
Oxidation forms reactive carbanion and vitamin K epoxide
Non-enzymatic carboxylation forms γ-carboxyglutamate
Epoxide is reduced to quinone and then hydroquinone
Warfarin prevents recycling of vitamin K
Excess vitamin K can overcome the inhibition because second reductase is insensitive to Warfarin
Activation of Protein C Pathway
Thrombin is inactivated by thrombomodulin on endothelial surface and also complex activates protein C and combines with protein S and inactivates factors 5 and 8
Inhibits coagulation cascade
Activation of Antithrombin
Antithrombin is serine protease inhibitor; inactivates any of the factors and inactivation activity is accelerated by cell surface heparin – derived from heparin and can stimulate antithrombin (inactivation of thrombin and factors)
Inhibits coagulation cascade
Factor Z and Z Related Protease Inhibitor
Factor Z and Z related protease inhibitor – inhibits factor XIa
Inhibits coagulation cascade
Fibrinolysis
Resolve fibrin clots via plasmin
Degrades fibrin and pulls apart clots
T-PA activated
Lysine residues bound to plasminogen to keep it in clot so readily available and cleave fibrin
Urokinase: ECM degradation and fibrin clot degradation
Regulation of Fibrinolysis: Prevention
Primary defense: alpha2 antiplasmin circulation in bloodstream to act on plasmin to inhibit it
Thrombin-activatable fibrinolysis inhibitor
(TAFIa) – acts negatively on plasmin so stops dissolution of the clots; is a carboxypeptidase; prevents plasmin from binding to fibrin
Plasminogen activator inhibitor: negatively affects t-PA so plasminogen cannot be converted to plasmin
Thrombin: Coagulation Action
Cleavage of fibrinogen to form fibrin
Activation of factor XIII (to crosslink fibrin)
Activation of factors V and VIII (Cofactors for factor Xa and factor IXa, respectively)
Activation of factor XI
Thrombin: Anti-Coagulation Action
Activation of protein C
Requires binding to thrombomodulin
Thrombin: Fibrinolysis Inhibition
Activation of thrombin-activatable fibrinolysis inhibitor (TAFI)
Requires binding to thrombomodulin
NO
Nitric Oxide (NO): inhibits platelet adhesion and aggregation by elevating levels of cGMP
Thrombomodulin
Thrombomodulin: glycoprotein that binds thrombin, which then cleaves protein C to yield activated protein C; this is in combination with protein S degrades factors Va and VIIIa, limiting their actions
t-PA
t-PA: tissue plasminogen activator; activates plasminogen to plasmin, which digests fibrin; the action of t-PA is opposed by plasminogen activator inhibitor-1 (PAI-1)
