GenPath RC - Key Points

Question 1

Briefly describe leukocyte recruitment

Answer 1

Loose attachment/rolling on the endothelium (selectins)
Firm attachment to endothelium (integrins)
Migration through interendothelial space

Question 2

What are the roles of TNF and IL-1 in regards to leukocyte recruitment?

Answer 2

Expression of selectins and integrins on endothelium

Question 3

What are the role of chemokines in leukocyte recruitment?

Answer 3

Increase the avidity of integrins for their ligands

Promote directional migration of leukocytes

Question 4

Endothelial injury exposes the _____________, platelets adhere via binding of platelet _____ receptor to _____.

Answer 4

underlying basement membrane
Gp1b
vWF

Question 5

The _______ receptors on activated platelets form bridging cross-links with fibrinogen –> platelet aggregation.

Answer 5

GpIIb/IIIa

Question 6

In vivo, factor _____ and ______ complex is the most important activator of factor IX

Factor ____ / _____ complex is the most important activator of factor X

Answer 6

VIIa and TF complex is the most important activator of factor IX

Factor IXa / VIIIa complex is the most important activator of factor X

Question 7

___ converts soluble ____ into fibrin

Answer 7

Thrombin (IIa) converts soluble fibrinogen (1) into fibrin (1a).

Question 8

Function of thrombin?

Answer 8

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

Question 9

Which factor covalently cross-links fibrin?

Answer 9

XIII

Question 10

Main player in fibrinolysis?

Answer 10

Plasmin - breaks down fibrin and interferes w/ polymerization

Question 11

How is plasmin generated?

Answer 11

Enzymatic catabolism of the inactive circulating precursor plasminogen (either by factor XII-dependent pathway or by plasminogen activators)

Question 12

Most common plasminogen activator?

Answer 12

t-PA

Synthesized primarily by endothelium and is most active when bound to fibrin

Question 13

List the antithrombotic properties of endothelium

Answer 13

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

Question 14

What causes thrombin to lose its ability to activate coagulation?

Answer 14

Thrombomodulin and endothelial protein C receptor bind thrombin and protein C

Question 15

What inhibits coagulation factors Va and VIIIa

Answer 15

Activated protein C / protein S complex

Question 16

Function and mechanism of TFPI

Answer 16

Like protein C, requires protein S as a cofactor

Binds and inhibits tissue factor / factor VIIa complexes

Question 17

Virchow’s triad

Answer 17

Abnormal blood flow (blood stasis / turbulence)
Hypercoagulability
Endothelial injury

Question 18

Mechanisms of coagulation w/ endothelial cell activation

Answer 18

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

Question 19

List common hypercoabulable states (primary genetic)

Answer 19

Factor V mutation
Prothrombin mutation
Increased levels of fVIII, IX, XI, or fibrinogen

Antithrombin III deficiency
Protein C, S deficiency

Question 20

What is the mechanism for Factor V mutation w/ hypercoagulable states?

Answer 20

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

Question 21

What is the mechanism of prothrombin mutation in hypercoagulable states

Answer 21

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

Question 22

Homocysteinemia

Answer 22

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

Question 23

Describve HIT heparin-induced thrombocytopenia syndrome

Answer 23

Formation of antibodies that recognize complexes of heparin and PF4 on the surface of platelets

Question 24

What is PF4?

Answer 24

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

Question 25

Mechanism of antiphospholipid antibody syndrome

Answer 25

Autoimmune disorder characterized by presence aPL autoantibodies

APL antibodies are directed against anionic membrane phospholipids or proteins associated w/ phospholipids
Proteins recognized by these antibodies include cardiolipin and B2-glycoprotein I

Question 26

Describe the difference between a red and white infarct

Answer 26

Red occur with venous

White infarcts occur w/ arterial occlusions

Question 27

Describe the mechanism of hyperglycemia and insulin resistance in septic shock

Answer 27

Cytokines such as TNF, IL1, glucagon, GH, glucocorticoids, and catecholamines drive gluconeogenesis

Pro-inflammatory cytokines cytokines suppress insulin release while promoting insulin resistance in the liber (likely by impairing GLUT-4)
**hyperglycemia decreases neutrophil function