GenPath RC - Key Points Flashcards
(27 cards)
Briefly describe leukocyte recruitment
Loose attachment/rolling on the endothelium (selectins)
Firm attachment to endothelium (integrins)
Migration through interendothelial space
What are the roles of TNF and IL-1 in regards to leukocyte recruitment?
Expression of selectins and integrins on endothelium
What are the role of chemokines in leukocyte recruitment?
Increase the avidity of integrins for their ligands
Promote directional migration of leukocytes
Endothelial injury exposes the _____________, platelets adhere via binding of platelet _____ receptor to _____.
underlying basement membrane
Gp1b
vWF
The _______ receptors on activated platelets form bridging cross-links with fibrinogen –> platelet aggregation.
GpIIb/IIIa
In vivo, factor _____ and ______ complex is the most important activator of factor IX
Factor ____ / _____ complex is the most important activator of factor X
VIIa and TF complex is the most important activator of factor IX
Factor IXa / VIIIa complex is the most important activator of factor X
___ converts soluble ____ into fibrin
Thrombin (IIa) converts soluble fibrinogen (1) into fibrin (1a).
Function of thrombin?
Induces platelet activation and aggregation via activation of PAR-1
Converts soluble fibrinogen to fibrin
Amplifies the coagulation process by activating factor XI and activating two critical cofactors: V and VIII
Stabilizes secondary hemostatic plug by activating fXIII (which covalently cross-links fibrin)
Functions as an anti-coagulant on a non-activated endothelium
Which factor covalently cross-links fibrin?
XIII
Main player in fibrinolysis?
Plasmin - breaks down fibrin and interferes w/ polymerization
How is plasmin generated?
Enzymatic catabolism of the inactive circulating precursor plasminogen (either by factor XII-dependent pathway or by plasminogen activators)
Most common plasminogen activator?
t-PA
Synthesized primarily by endothelium and is most active when bound to fibrin
List the antithrombotic properties of endothelium
Platelet inhibitor effects: NO, prostacyclin (PGI2), ADP
Anticoagulant effects: normal endothelium shields coagulation factors from TF. Express factors that oppose coagulation (thrombomodulin, endothelial protein C receptor, TFPI)
Fibrinolytic effects - normal endothelial cells secrete t-PA
What causes thrombin to lose its ability to activate coagulation?
Thrombomodulin and endothelial protein C receptor bind thrombin and protein C
What inhibits coagulation factors Va and VIIIa
Activated protein C / protein S complex
Function and mechanism of TFPI
Like protein C, requires protein S as a cofactor
Binds and inhibits tissue factor / factor VIIa complexes
Virchow’s triad
Abnormal blood flow (blood stasis / turbulence)
Hypercoagulability
Endothelial injury
Mechanisms of coagulation w/ endothelial cell activation
Procoagulant changes - endothelial cells activated by inflammatory cytokines downregulate the expression of thrombomodulin —> enhances the procoagulant and proinflammatory actions of thrombin . Inflammed endothelium also downregulates anticoagulants (protein C and TFPI)
Antifibrinolytic effets: activated endothelial cells secrete PAIs and limit fibrinolysis and downregulate the expression of t-PA
List common hypercoabulable states (primary genetic)
Factor V mutation
Prothrombin mutation
Increased levels of fVIII, IX, XI, or fibrinogen
Antithrombin III deficiency
Protein C, S deficiency
What is the mechanism for Factor V mutation w/ hypercoagulable states?
Arg to Gln substitution in amino acid residue 506 leading to resistance to activated protein C
Essentially a single nucleotide mutation in factor V that is called factor V leiden
What is the mechanism of prothrombin mutation in hypercoagulable states
G20210A noncoding sequence variant leading to increased prothrombin levels
Single nucleotide chanage in the 3’ untranslated region of the prothromboin gene is another common mutation
Homocysteinemia
Elevated levels of homocysteine may be inherited or acquired
Caused by inhierited deficiency of cystathione B-synthestase
Acquired causes include vitamin B6, B12, and folic acid deficiency
Is a hypercoagulable state
Describve HIT heparin-induced thrombocytopenia syndrome
Formation of antibodies that recognize complexes of heparin and PF4 on the surface of platelets
What is PF4?
PF4 is a protein that is found in platelet alpha granules and is released on activation of platelets
Released PF4 binds to heparin and undergoes a conformational change that results in the formation of a neoantigen against which IgG antibodies are formed
PF4-IgG immune complex attaches to and cross-links the Fc receptors on teh platelet surface —> platelet activation/aggregation
