01 Biology Of Hemostasis Flashcards
Four major physiologic events in hemostasis?
Vascular constriction
Platelet plug formation
Fibrin formation
Fibrinolysis
What is the initial response to vessel injury?
Vasoconstriction
Substances that promote vasoconstriction?
Thromboxane A2 (TXA2)
Endothelin
Serotonin (5-HT)
Bradykinin and Fibrinopeptides
Normal circulating number of platelets?
150,000-400,000
Lifespan of platelets?
7-10 days
What happens in primary hemostasis?
Injury to the intimate layer in the vascular wall exposes subendothelial collagen to which platelets adhere.
Von Willebrand factor (vWF), a protein in the subendothelium, binds to glycoproteins I/IX/V on the platelet membrane.
Following adhesion, platelets initiate a release reaction that recruits other platelets to seal the disrupted vessel.
What is the final event in primary hemostasis?
Following adhesion, platelets initiate a release reaction that recruits other platelets from the circulating blood to seal the disrupted vessel.
Principal mediators in platelet aggregation?
Adenosine diphosphate
Serotonin
Can hemostasis occur in heparinized patients?
Yes.
Platelet aggregation is reversible and is not associated with secretion. Heparin does not interfere with this reaction, hence hemostasis can occur in the heparinized patient.
Origin of thromboxane A2 (TXA2)?
Arachidonic acid released from the platelet membranes is converted by cyclooxygenase to prostaglandin G2 (PGG2) and then to prostaglandin H2 (PGH2).
This in turn is converted to TXA2.
Effects of TXA2?
Thromboxane A2 has potent vasoconstriction and platelet aggregation effects.
Arachidonic acid may also be shuttled to adjacent endothelial cells and converted to prostacyclin (PGI2). Actions of PGI2?
PGI2 is a vasodilator and acts to inhibit platelet aggregation.
How is platelets cyclooxygenase affected by medications?
Platelet cyclooxygenase is irreversibly inhibited by aspirin and reversible blocked by NSAIDs.
But it is not affected by COX-2 inhibitors.
In the second wave of platelet aggregation, a release reaction occurs in which several substances (ADP, Ca2+, serotonin, TXA2, alpha-granule proteins) are discharged.
What is the required cofactor for this process?
Fibrinogen, which acts as a bridge for the GP IIb/IIIa receptor on the activated platelets.
The release reaction results in compaction of the platelets into a plug. This is IRREVERSIBLE.
Thrombospondin is a protein secreted by the alpha-granules. What is its role in the second wave of platelet aggregation?
It stabilizes fibrinogen binding to the activated platelet surface and strengthens platelet-platelet interactions.
Which substances inhibit the second wave of platelet aggregation?
Aspirin
NSAIDs
Cyclic adenosine mono phosphate (cAMP)
Nitric oxide (NO)
The intrinsic pathway begins with?
The activation of factor XII, which subsequently activates factor XI, IX, and VIII.
Why is the intrinsic pathway called as such?
In this pathway, each of the primary factors is “intrinsic” to the circulating plasma, whereby no surface is required to initiate the process.
What initiates the extrinsic pathway?
Tissue factor (TF) is released or exposed on the endothelial surface, binding to circulating factor VII, facilitating its activation to VIIa.
The common pathway begins with?
The activation of factor X to Xa (in the presence of VIIIa).
Subsequently, Xa (with the help of factor Va) converts factor II (prothrombin) to thrombin, and then factor I (fibrinogen) to fibrin.
When does clot formation occur?
Clot formation occurs after fibrin monomers are cross-linked to polymers with the assistance of factor XIII.
An elevated activated partial thromboplastin time (aPTT) is associated with which arm of the cascade?
Intrinsic arm (II,IX, X, XI, XII)
An elevated prothrombin time (PT) is associated with which arm of the cascade?
Extrinsic arm (II, VII, X)
Vitamin K deficiency or warfarin use affects which factors?
Factors II, VII, IX, X (27910)
The primary pathway for coagulation is initiated by?
Tissue factor (TF) exposure following subendothelial injury.
The prothrombinase complex, which converts prothrombin to thrombin, is formed by?
Factor Xa
Factor Va
Calcium
Phospholipid
Actions of thrombin?
Thrombin is involved with the conversion of fibrinogen to fibrin, and activation of factors V, VII,VIII, XI, and XIII.
The intrinsic factor complex is formed by?
Factor VIIIa combined with IXa
Role of thrombin-activatable fibrinolysis inhibitor (TAFI)?
Acts to stabilize the resultant fibrin clot.
Mechanisms to prevent clot propagation beyond the site of injury?
- Feedback inhibition (deactivates enzyme complexes leading to thrombin formation)
- Tissue plasminogen activator (tPA) release (cleaves plasminogen to initiate fibrinolysis)
- APC system (forms complex with cofactor protein S, cleaving Va and VIIIa, preventing TF-VIIa or prothrombinase complexes)
Genetic mutation in which factor V is resistant to cleavage by APC, thereby remaining active as a procoagulant, and leading to venous thromboembolic events?
Factor V Leiden
Degradation of the fibrin clot is accomplished by?
Plasmin
Effects of fibrinolysis?
Allows restoration of blood flow during the healing process following injury.
It begins at the same time clot formation is initiated.
Mechanisms to keep fibrinolysis in check?
- Plasmin is inhibited by alpha2-antiplasmin
- Circulating Plasmin is inhibited by alpha2-antiplasmin, tPA or urokinase.
- TAFI removes lysine residues from fibrin that are essential for binding plasminogen.
