Hemostasis and Coagulation Pathways

Question 1

what is hemostasis? thrombosis?

Answer 1

regulated process that maintains blood in a fluid state in normal vessels

pathological counterpart of hemostasis; results in blood clot (thrombus) formation within vessels

Question 2

endothelium antiplatelet properties

Answer 2

done by intact endothelium

produce NO, prostacyclin (PGI2) and adenosine diphosphatase (Adp)

NO and PGI2 bind to activated platelets and inactivate receptors, inhibiting platelet adhesion to ECM; synthesis stimulated by thrombin and cytokines

Adp degrades ADP which favors attachment of platelets to ECM

Question 3

endothelium anticoagulant properties

Answer 3

express heparin sulfate (HS), thombomodulin (TM), protein S and tissue factor pathway inhibitor (TFPI)

HS binds/activates antithrombin III (AT III); AT III inactivates thrombin (T), Xa and IXa

TM binds T, activates protein C; activated protein C inhibits Va and VIIIa

protein S is a cofactor for protein C

TFPI directly inhibits VIIa and Xa

Question 4

endothelium fibrinolytic properties

Answer 4

tissue-type plasminogen activator (t-PA)

synthesized by endothelial cells; t-PA activates plasminogen -> plasmin, plasmin degrades fibrin to fibrin degradation product (FDP), dissolves thrombin

Question 5

list 4 steps of hemostasis

Answer 5

1) primary hemostasis: localized platelet plug formed at site of injury
2) secondary hemostasis: initial platelet plug enlarged and stabilized with fibrin matrix, forms clot
3) antithrombosis: once stable clot formed, additional clot formation ceases
4) fibrinolysis: removal of clot and restoration of normal blood flow through vessel

Question 6

von Willebrand factor (vWF)

Answer 6

response to injury
secreted by endothelial cells from basal membrane onto ECM
forms thin “varnish” over ECM
ligand for GpIbR on platelets

Question 7

describe steps of primary hemostasis

Answer 7

1) platelets bind via GpIbR to vWF on ECM
2) platelets activate, release thromboxane A2, delta and alpha granules

TX A2: vasoconstrictor, platelet aggregator

delta granules: contain serotonin, ADP, and calcium

alpha granules: contain coagulating factors, fibrinogen, platelet-derived growth factor (PDGF)

3) platelets aggregate, associate through fliopodia binding fibrinogen linker molecules with GpIIb/IIIaRs
4) after 3-5 minutes, blood flow arrested, primary plug formed

Question 8

describe steps of secondary hemostasis

Answer 8

1) aggregated platelets express phospholipids, forming platform that greatly accelerates intrinsic and common clotting pathways
2) clotting cascade results in fibrin polymerization through activation of thrombin (IIa)
3) fibrin deposited on top of and within platelet plug to cement into place -> secondary plug
4) 5-10 minutes after insult, secondary plug reinforced

Question 9

describe steps of antithrombosis

Answer 9

performed by intact endothelial cells

1) NO/prostacyclin inhibit adherence/aggregation of activated platelets
2) HS binds III (AT), inactivates IIa, IXa and Xa
3) TM binds thrombin (IIa), activates protein C, deactivates Va and VIIIa
4) TFPI inactivates VIIa complexes

Question 10

describe extrinsic pathway

Answer 10

blood contacts injured tissue -> IIIa (tissue thromboplastin) interacts with VII (proconvertin) and Ca2+ -> X (Stuart)

Question 11

describe intrinsic pathway

Answer 11

exposed collagen activates XII (Hageman) -> XI (plasma thromboplastin antecedent) + IV + Ca2+ -> IX (Christmas) + VIII (antihemophilic) + Ca2+ -> X (Stuart)

Question 12

describe common pathway

Answer 12

Xa + Ca2+ V (accelerin) -> (prothrombin activator) -> prothrombin to II (thrombin) -> cleaves I (fibrinogen) into Ia (fibrin), complexes w/ XIII (fibrin-stabilizing factor) and Ca2+ to form fibrin polymers
thrombin feeds back positively on prothrombin activator

Question 13

roles of thrombin

Answer 13

cleaves fibrinogen -> fibrin
activates XIII
induces platelet aggregation
induces TX A2 production
activates ECs to express adhesion molecules, t-PA, NO, PGI2, and PDGF
activates leukocytes

Question 14

describe fibrinolysis

Answer 14

circulating plasminogen -> (t-PA) -> plasmin

plasmin degrades fibrin into fibrin degradation product (FDP)

Question 15

thrombosis - what is it and why is it dangerous?

Answer 15

thrombosis: pathophysiologic process that leads to formation of thrombus (abnormal large clot)
failure of one or more physiologic mechanisms of antithrombosis

two major pathologies: vascular obstruction or embolism (clot fragment within flow of blood stream)

Question 16

diagram full coagulation pathway

Answer 16

see slide 40

Question 17

immediately following injury and before primary hemostasis, what events occur?

Answer 17

damaged endothelium releases endothelin, stimulates vasoconstriction
damaged smooth muscle undergoes myogenic constriction

Question 18

Glanzmann thrombasthenia - cause, effects

Answer 18

GpIIb/IIIaR deficiency

platelets unable to aggregate -> primary hemostasis inhibited -> inability to clot

Question 19

Bernard-Soulier syndrome - cause, effects

Answer 19

GpIbR deficiency

platelets unable to bind vWF -> platelet binding/aggregation inhibited -> inability to clot

Question 20

dabigatran - action

Answer 20

inhibits thrombin recruitment/activation of platelets

Question 21

plavix (clopidogrel) - action

Answer 21

inhibits ADP recruitment/activation of platelets

Question 22

aspirin - action

Answer 22

inhibits COX-1 formation of TX A2

Question 23

reopro (abciximab) - action

Answer 23

GpIIb/IIIaR antagonist, inhibits platelet aggregation