Flashcards in Exam #2: Hemodynamics II Deck (53):
What balance must be maintained in hemostasis? What is the function of hemostasis?
The balance between prothrombosis & antithrombosis
Function is to maintain blood in a fluid fluid state in the blood, while allowing for the rapid formation of a hemostatic clot in response to vascular injury
What are the three general components that contribute to hemostasis?
1) Endothelium/ vascular wall
2) Platelets-- bricks
3) Coagulation cascade & fibrin--mortar/ cement
Describe the sequence of clot formation.
1) Injury= transient vasoconstriction (endothelin mediated)
2) Endothelial damage= exposure of ECM causing platelet activation
3) Tissue factor + Factor VII-->Thrombin-->Fibrin
4) Fibrin & platelets from a clot, plugging the defect and preventing blood loss
What are the four stages of normal hemostasis following vascular injury?
2) Primary hemostasis
3) Secondary hemostasis
4) Thrombus & antithrombotic events
Outline the molecular events that cause transient vasoconstriction.
Injury causes the release of "endothelin" from the injured blood vessel, which causes a reflex vasoconstriction
Outline the molecular events that occur in primary hemostasis.
- Injury exposes the ECM
- Exposed ECM--> platelet activation & extravasation to the site of injury forming a "hemostatic plug"
Outline the molecular events that occur during secondary hemostasis.
- Tissue Factor i.e. Factor III or "Thromboplastin" is exposed during injury
- Tissue Factor + Factor VII--> activation of coagulation cascade & thrombin formation
- Thrombin cleave Fibrinogen to Fibrin
Outline the molecular events that occur during thrombus formation and antithrombosis.
- Fibrin + activated platelets form a "permanent plug"
- With the permanent plug formed, antithrombic mechanisms are set in motion to limit the thombus ONLY TO THE SITE OF INJURY
- Limiting thrombus is "tissue plasminogen activator" i.e. "t-PA" mediated
What factors activate the endothelium and shift the function to the procoagulant state?
Trauma obviously, but additionally:
1) Infectious agents
2) Hemodynamic forces i.e. HTN
4) Plasma mediators
What are the antithrombic mechanisms of the endothelium?
Normally, endothelial cells function in an anticoagulant fashion. This state is maintained by three general mechanisms:
1) Anti-platelet: blocking platelet activation & aggregation
- Barrier to thrombogenic subendothelial ECM
- Secretion of prostacyclin (PGI2) & NO inhibit platelet
- Secretion of adenosine diphosphatase, breaksdown ADP that causes platelet aggregation
2) Anti-coagulant: blocking coagulation cascade
- Heparin-like molecules= cofactors for antithrombin
- Thrombomodulin= converts thrombin to an anticoagulant
3) Fibrinolytic: lysing clots
- Production of tPA, a protease the degrades fibrin
What are the prothrombic mechanisms of the endothelium?
Trauma, inflammation, and other events can cause the endothelium to transition to a prothrombic state. These mechanisms are opposite of the antithombic mechanisms:
1) Platelet effects
- vWF, a cofactor for platelet binding to the ECM
- Cytokine or bacterical endotoxin induced production of
Tissue Factor, that activates the extrinsic clotting cascade
- Secretion of t-PA inhibitors, called plasminogen activator inhibitors (PAIs)
What are platelets? What produces platelets?
Platelets are anucleate fragments of megakaryocytes produced in the bone marrow; they contain
- alpha granules
- dense granules
What are the three steps of platelet activation?
2) Secretion of granules and activation
What is the moleular mechanism that mediates platelet adherence?
ECM vWF + Platelet glycoprotein Ib receptors= firm adherence
*****This is where the genetic defect is in Von Willebrand's Disease that leads to the bleeding disorder (Mom)*****
What does platelet adhesion lead to?
Secretion i.e. release of platelet granules (alpha & dense)
What are the important mediators released by platelets? What are the functions of these mediators?
1) Ca++= critical for coagulation cascade
2) ADP= platelet aggregation
4) Platelet Factor IV-->inactivation (part of maintaining a local response?)
What causes platelet aggregation?
ADP & thromboxane A2released by platelets
Outline the process of platelet aggregation. What is the role of fibrinogen?
1) ADP triggers a conformation change in platelet GpIIb & GpIIIA receptors
2) Conformational change induces binding to fibrinogen
3) Fibrinogen binding to receptors on adjacent platelets= aggregation
What is the mechanism of action of plavix?
Inhibition of ADP induced platelet binding
What is the end goal of the coagulation cascade?
Formation of thrombin that cleaves circulating fibrinogen to fibrin i.e. the "mortar" that seals platelets & forms the permanent plug
What is a coagulation factor complex? Where does it assembly? What is required for its assembly?
A coagulation factor complex is:
Enzyme (activated coagulation factor) + Proenzyme (inactivated coagulation factor) + Ca++ = complex
- Ca++ is the cofactor that holds the two coagulation factors together
- Assembly occurs on a phospholipid surface
What is the difference between serum and plasmin?
Serum= blood without clotting factors
Plasmin= blood with clotting factors
What is the function of thrombin?
- Conversion of fibrinogen to fibrin monomer
- Fibrin is the "glue" for the platelet plug
Draw the coagulation cascade.
What is a Prothrombin time (PT)?
Measurement of the extrinsic pathway
What drug will prolong PT?
What is a Partial Thromboplastin Time (PTT)?
Measurement of the intrinsic pathway--normally this is longer than the PT
What drug prolongs the PTT?
What is the mnemonic to remember the intrinsic pathway?
List the anticoagulants.
1) Antithrombin III
2) Protein C
What is the mechanism of antithrombin III?
Direct inactivation of serine proteases:
What is the mechanism of Heparin?
Potentiation of antithrombin III
What is the mechanism of protein C?
Inhibition of Va and VIIIIa
What is the function of Protein S?
Enhancement of protein C
What is thrombomodulin?
- Activated by thrombin
- Binds to thrombin and alters its conformation
- Conformational change leads to activation of protein C (anticoagulant)
What is tissue pathway factor inhibitor?
A protein produced by the endothelium that inactivates TF- Factor VIIa
What inactivates free plasmin?
Circulating alpha-2 antiplasmin
What is the function of plasminogen activator inhibitor (PAI)
Inactivation of tPA
What activates PAI?
Thrombin & various cytokines
What is the function of plasmin? What is the precursor of plasmin?
- Breakdown of fibrin
What substances activate plasminogen?
2) tPA i.e. "Tissue Plasminogen Activator"
What is the difference between a thrombus and an embolus?
Thrombus= blot clot that forms abnormally within a blood vessel
Embolus= dislodged blood clot that travels through the bloodstream
Where is Heparin produced naturally?
Basophils and mast cells to prevent formation and extension of blood clots
How is Heparin administered?
SubQ or IV, NEVER PO
What is the mechaism of Heparin?
Potentiation of Antithrombin III
What is Warfarin?
Oral medication that is a synthetic derivative of coumarin
Why would you put a patient on Warfarin vs. Heparin?
Heparin= starts working immediately; therefore, it is used post-op to prevent DVT, PE...etc.
Warfarin= takes time to start working; therefore, it is used for long-term anticoagulant therapy
What are the Vitamin K dependent clotting factors produced by the Liver?
Which pathway is inhibited by Warfarin & which pathway is inhibited by Heparin? How are these measured?
Warfarin= Extrinsic & PT
Heparin= Intrinsic & PTT
Aside from coumadin and heparin, what are the other classes of anticoagulant drugs?
- Direct Thrombin Inhibitors
- Direct Factor X inhibitors
- Tissue Factor Pathway Inhibitors
What is Dabigatran?
Direct Thrombin Inhibitors
What is Rivaroxaban & apixaban?
Direct Factor Xa Inhibitors