Block 6: Path - 11/29: Hemostasis And Thrombosis

Front 1

In blood clot formation, what is the purpose of vasoconstriction? How is it mediated?

Back 1

Vasoconstriction: momentarily stops blood loss

Endoth cells release ENDOTHELIN

Platelets release THROMBOXANE A2

both of these are vasoconstrictors

Front 2

What is it about endothelial cell injury that induces platelet adhesion? What receptors are required?

Back 2

Injury exposes SUBENDOTHELIAL MATRIX (collagen)

GpIb Receptor on platelet and vonWillebrand factor on subendothelium (BRIDGE)

Front 3

Defect in VW factor?

Back 3

VW Dz

Front 4

Defect in GpIb?

Back 4

Bernard Soulier Syndrome

Front 5

What do platelets do when activated to recruit more platelets?

What enzyme is activated? What chemical does this produce?

Back 5

Undergo shape change and release reaction (via open canalicular system)

Activates Phospholipase A2
(AA-->PGG2-->THROMBOXANE A2)

Thromboxane A2 not only vasoconstricts, but also is a platelet agonist (aggregation)

Front 6

How do endothelial cells moderate platelet aggregation and vasoconstriction? Describe the reaction.

Back 6

Phosphopliase-->AA-->PGG2-->PROSTACYCLIN

Prostacylin inhibits plateley aggregation and induces vasodilation

Front 7

How does the mechanism of Cox-1 inhibitors differ from that of Cox-2 inhibitors?

Back 7

Cox-1 inhibitors inhibits platelet aggregation (required to produce PGG2 which makes Thromboxane A2)

Cox-2 inhibitors inhibit PGG2 formation in ENDOTHELIAL CELLS which inhibit Prostacyclin formation and decreases inhibition of platelet aggregation (pro-thrombic effect)

Front 8

Cox-2 inhibitor suffix?

Back 8

-coxib

Front 9

What receptors and bridges are required for platelet aggregation?

Back 9

Act'd platelets express GpIIb/IIIa receptor

Liver increases fibrinogen production

FIBRINOGEN serves as bridge

Front 10

GpIIb/IIIa receptor defect?

Back 10

Glanzmann's Thrombasthenia

Front 11

Effect of GpIIb/IIIa inhibitor?

Back 11

potent anticoagulant

Front 12

What is primary hemostasis? What steps are involved?

Back 12

Formation of unstable platelet plug.

Involves vasoconstriction, platelet adhseion, shape change, release rxn, aggregation

Front 13

What is petechiae?

Back 13

microhemorrhages (spontaneous), show up as small red spots on skin

due to thrombocytopenia!!!

Front 14

What is purpura?

Back 14

When petechiae coalesce (larger blood spots)

Front 15

What does bleeding time measure?

Back 15

Measure primary hemostasis, i.e., formation of an unstable platelet plug

Front 16

What is the purpose of fibrin?

Describe the extrinsic and intrinsic pathways leading to its formation.

Back 16

Fibrin is end product of coagulation cascade; necessary for formation of stable blood clot

Extrinsic PW:
Tissue Factor released from damaged endoth cell
Factor 7

Intrinsic:
Factor 12 (Hageman)
Factor 11, 9, 8

Both of these lead to COMMON PW:
Factor 10, 5, Ca2+, Phospholipase
Prothrombin (Factor 2) to Thrombin (2a)
Fibrinogen to Fibrin

Front 17

Describe the cross-talk between the extrinsic and intrinsic pathways.

Back 17

Factor 7 of EPW can activate Factor 9 on IPW

Front 18

Factor 12 deficiencies result in?

Back 18

Thrombosis! (not bleeding disorders; it's not the only factor of clotting)

Front 19

Hemophilia A vs Hemophilia B (factor deficiencies)

Back 19

Hemo A: Factor 9 deficiency
Hemo B: Factor 8 deficiency

Front 20

Tests to assess EPW and IPW of coaguln cascade. Names and how they differ.

Back 20

EPW: Prothrombin Time (PT) - time from add'n of tissue factor to formn of clot; aka INR

IPW: Partial Thromboplastin Time (PTT) add contact activating substance (for XII-->XIIa) to clot

Front 21

Fibrinogen-->Fibrin requires?

Back 21

THROMBIN
Factor 13 (Fibrin stabilizing factor)
Calcium

Front 22

Effect of hemophilia on bleeding time?

Back 22

NO effect. bleeding time measures unstable platelet plug formation time.

Front 23

Effect of liver disease on clotting?
Vitamin K deficiency?

Why?

Back 23

Liver dz: no clotting factors

Vit K: Factors 2, 7, 9, 10 require Vit K for post-translnl activn

Front 24

Mechanism of warfarin sodium (Coumadin)

Back 24

inhibits oxidation of vitamin K (blocks post-translnl mods of vit K)

NOTE: not a total block, just a decrease

Front 25

What does plasminogen-->plasmin require? Role of plasmin?

Back 25

Requires PLASMINOGEN ACTIVATORS

Plasmin chews up fibrin

Front 26

What are the two subtypes of plasminogen activators? How do they differ?

Back 26

Urokinase-like PA: activates plasminogen in fluid phase

Tissue-Type PA: in endothelial cells

Both activate plasminogen on surface of fibrin

Front 27

Role of alpha2-antiplasmin?

Back 27

Inactivates free plasmin in blood

Front 28

Streptokinase is an example of what?

Back 28

Therapeutic Plasminogen Activator

TPA's are expressed by ENDOTHELIAL CELLS

Front 29

What would overwhelming stimulus to the coagulation cascade result in?

Back 29

Consumptive coagulopathy-->bleeding due to decreased clotting factors, decreased platelets, increased fibrinolysis

Front 30

Role of Antithrobmic Factor III?

Back 30

Inhibits Factors 12, 11, 10, 9, and thrombin

ACCELERATED by HEPARIN

ON ENDOTHELIAL CELLS

Front 31

Role of thrombomodulin?

Back 31

Present on endothelial cells, when thrombin binds, activates PROTEIN C

Prot S is a co-factor of PROT C

Act'd PROT C (APC) degrades Factors 8, 5

Front 32

How do uninjured endothelial cells prevent platelet aggregation?

Back 32

Secrete PGI2 and NO (potent vasodilators and inhibitors of platelet aggregation)

Front 33

What are two ways the endothelial cells promote coagulation?

Back 33

1) If injured, release Tissue Factor (initiates blood coaguln cascade)

2) Binding sites for Factors 9 and 10; augments their activity

Front 34

How does arterial thrombosis arise? Consequences? Fates of the thrombi?

Back 34

Turbulent flow due to arterial narrowing

Platelets and leuks contact abnormal surface (no shearing forces), initiates PLATELET AGGREGATION and formation MURAL THROMBUS

Fates:
Act as nidus (nest)
Incorp'd into cell wall
EMBOLIZE!!

Front 35

Red vs White Infarct

Back 35

Red (Hemorrhagic): due to venous occlusion in area with single venous outflow (testis, ovary), loose tissues (lungs), areas with dual circuln (lung, sm intest) when FLOW RE-ESTABLISHED

White (pale) infarct: ARTERIAL occlusion in solid tissue (heart, spleen, kidney) where hemorrhage is limited

Front 36

How does venous thrombosis arise? Fates?

Back 36

Small deposits (commonly in valve cusp pockets), form nidus, grow in direcn of flow, occlude lumen; slow flow

Fates:
Lysis (resoln)
Organizn (new capillary channels formed, aka RECANALIZATION)
Embolization

Front 37

What is hypercoaguability? 2 causes?

Back 37

Spontaneous thromboses in pts under 50

Mutation in Factor 5 (Leiden) gene-->APC resistance (decreased inactivation of Factor 5)

Mutation in protrhombin gene

(Hereditary resistance to Prot C; a natural anticoagulant)