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20 Cards in this Set
- Front
- Back
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Tissue factor
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Is trigger
Transmembrane protein Found everywhere -Except in the bloodstream -Deletion is lethal Cofactor for Factor VIIa activity -Factor X activation – static system -Factor IX activation – flowing system TF-VIIa is rapidly inhibited by TFPI (Tissue factor pathway inhibitor) |
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Fibrin clot formation
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Requires thrombin
-Major coagulation effector enzyme -Converts Fibrinogen to Fibrin -Activates Factor XIII --FXIIIa crosslinks Fibrin (gamma crosslinks, then alpha crosslinks) -Activates Platelets |
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Fibrin and Fibrinogen
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Fibrinogen
-Soluble, digested by plasmin Fibrin -Weak clot, easily digested by plasmin Gamma crosslinked Fibrin -Strong clot, can be digested by plasmin Alpha crosslinked Fibrin -Strong clot, resists plasmin digestion |
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Coagulation cascade
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TF-VIIa cofactor for FIX to FIXa
FIXa cofactor for FX to FXa FXa cofactor for FII to Thrombin Thrombin cofactor for FVIII to FVIIIa which amplifies FX to FXa Thrombin also cofactor for FV to FVa which amplifies FII to thrombin (by 300k fold) Once cascade begins TF-VIIa is a direct cofactor for FX to FXa |
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Natural anticoagulation
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Antithrombin 3
-inhibitor of Thrombin -inhibitor of FXa -inhibitor of FIXa Protein C System -Protein S -Thrombomodulin |
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Heparin cofactor activity
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Unfractionated heparin
-accelerates the inhibition of thrombin by AT3 to form TAT (thrombin antithrombin complex) Unfractionated heparin and low molecular weight heparin accelerate the inhibition of FXa by AT3 forming the XAT (ten antithrombin complex) -major funciton Neither affects FIXa inhibition by AT3 |
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Protein C system
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Thrombin (IIa) combines with Thrombomodulin (TM) on the surface of endothelial cells as the thrombomodulin IIa complex (TM-IIa)
TM-IIa converts Protein C (PC) into activated Protein C (aPC) aPC converts FVa to FVi (inactive form) -requires cofactor of Protein S -downregulates production of thrombin Overall, excess thrombin leads to negative feedback via Protein C |
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Fibrinolysis
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Triggered by aPC
Plasmin is the effector enzyme -Relatively non-specific serine protease Fibrin specificity is conferred by activation mechanism -aPC binds to receptor on endothelial cell and triggers release of tPA (tissue plasminogen activator) -tPA requires fibrin as a cofactor to convert plasminogen to plasmin (confers fibrin specificity) -plasmin then degrades fibrin |
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Defective hemostasis
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Decreased thrombin/plasmin ratio
Severe deficiency of a single factor -Hemophilia -Immune inhibitors Combined deficiency of many factors -Vitamin K deficiency -Liver disease Anticoagulation -Warfarin -Heparin -Argatroban, Refludan, Angiomax, dabigatran Excess Fibrinolysis -Liver disease -Thrombolytic therapy |
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Hydraulic forces and tamponade
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Pressure difference across the vascular defect
-assumes external pressure is 0 -artery = 80mmHg -vein 10 mmHg Tamponade -In a closed space, as bleeding continues, external pressure rises to match internal pressure -Effectiveness depends on pressure difference -If external pressure rises above a critical value all blood flow ceases and other structures are compromised giving a “compartment syndrome” |
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Shear forces
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Shear forces increase as
-Linear velocity increases --Activated coagulation factors are washed away -Viscosity increases -Vessel radius decreases -Flow changes from laminar to turbulent --High flow rates --Vessel irregularities Need to localize fibrin deposition -Platelets are activated by thrombin -Activated platelets --Promote coagulation --Stick to Fibrin --Stick to each other --Stick to subendothelial VWF --Stickiness increases with shear rate |
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Thrombosis overview
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Conceptualize as hemostasis within the vessel rather than outside the vessel
Biochemistry pretty much the same as hemostasis Thrombosis risk is the converse of bleeding risk Usually triggered by localized “patch” of exposed Tissue Factor Think of it as an ectopic hemostatic plug Thrombosis requires thrombin activity to exceed plasmin activity Thrombosis occurs with -Increased thrombin generation --Coagulation factor inhibitor deficiencies -Decreased plasmin generation -Increased platelet procoagulant function --Thrombocytosis --Activated platelets |
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Venous thrombosis
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Virchow’s triad:
Alteration in the vessel -Damaged endothelium --Exposes tissue factor --Exposes collagen/VWF -Alteration in the blood --Increased thrombin generation --Decreased plasmin response -Stasis --Valve pockets --Area of hypoxia |
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Arterial thrombosis
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Atherosclerotic plaques as focus
-Tissue factor exposure Platelets are central -High shear setting -VWF involved Coagulation involved in thrombus growth |
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Thrombophilic factors
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Inherited
-Protein C, Protein S, AT3 deficiencies -FV Leiden, G20210A mutations Congenital -Factors II, VII, VIII, IX, XI, VWF, homocysteine Acquired -Age -Lupus anticoagulant, DIC -Obesity, sedentary lifestyle, smoking -Malignancy, surgery, pregnancy -HIT/HITT |
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DIC overview, mortality, sequence
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TF on circulating monocytes
-Activation by lipopolysaccharide – sepsis Mortality from DIC -Stage 1 1% -Stage 2 5% -Stage 3 60% Sequence of events -Stage 1 becomes Stage 2 -Stage 2 becomes Stage 3 Recognize and treat Stage 1 -High index of suspicion Prevent Stage 1 -Use prophylactic heparin in high risk settings |
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DIC Stage 1
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The hypercoagulable state
AT3 is adequate to control the coagulation cascade But:- -Factors V and VIII are being activated to FVa and FVIIIa by thrombin --Procoagulant effectiveness increases --More thrombin produced for a given stimulus -Circulating platelets are activated Risk of thrombosis is increased Control coagulation to regulate process Low dose heparin -Amplifies AT3 effectiveness -Shuts down thrombin generation -Reduces risk of thrombosis Anti-platelet agents -GP IIb/IIIa inhibitors block platelet aggregation -ASA, Clopidogrel (Plavix) block platelet activation |
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DIC Stage 2
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Early or mild DIC/Consumption coagulopathy
AT3 has been consumed -Excess thrombin is produced -The protein C system becomes activated -aPC inactivates FVa and FVIIIa --FV and FVIII deficiencies result Activated platelets are removed from the circulation -Thrombocytopenia Risk of bleeding is increased Replace missing coagulation factors V and VIII -Cryoprecipitate --FVIII and Fibrinogen -Platelets --FV Replace AT3 -Concentrate or bank plasma Then low dose heparin to control thrombin generation -Increases risk of bleeding Antiplatelet agents -Increases risk of bleeding -generally don't use |
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DIC Stage 3
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Late or Severe DIC/Consumption Coagulopathy
aPC inhibitor has been consumed Fibrinolysis has been activated Free Plasmin -Dissolves hemostatic plugs -Reduces the thrombin/plasmin ratio -Digests most coagulation factors -Digests Fibrinogen -Digests platelet surface receptors Defective hemostasis and rebleeding of old wounds Need to inhibit plasmin -AMICAR -High risk of fatal thrombosis Need to inhibit Thrombin -Heparin and friends -High risk of fatal bleeding Need to replace coagulation factors -Plasma -Concentrates --Cryoprecipitate --Platelets --AT3 --Prothrombin complex |
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Intrinsic vs Extrinsic pathway
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Triggers
-Intrinsic: Hageman factor (FXII) -Extrinsic: Tissue factor Common Endpoint -Activation of Thrombin -Subsequent conversion of: fibrinogen to fibrin (with Thrombin as a cofactor) Fibrin fibers stabilize clot XII and XI deficiencies don't lead to bleeding disorders TF and FVII lead to fatal bleeding disorders Seen that in open system with FXII/XI deficiencies, FVIIa can activate FIX to FIXa and doesn't activate FX to FXa |
