Exam #2: Hemostasis Flashcards
What are the 5 different components of the hemostasis system? What are their main functions?
1) Vascular= constriction that reduces blood flow to prevent blood loss & slows platelets for better adherence
2) Platelet= form platelet plugs to prevent blood loss & secrete vasoconstrictors
3) Coagulation= forms fibrin clots & further activates platelets
4) Anti-coagulation= reduce coagulation
5) Fibrinolytic= dissolves unnecessary clots
What can a deficiency in any of the 5 systems cause?
Hemorrhaging (Hemophilia)
Clotting (Thrombosis)
What responds first when there has been tissue damage?
Vascular System
Outline the vascular response to tissue damage.
1) Damaged tissue secretes factors that cause vasoconstriction
2) Platelets become activated
3) Activated platelets secrete Thromboxane A2 & Serotonin, leading to further vasoconstriction
Vasoconstriction prevents blood loss & slows flow to give platelets a better chance of adhering.
How does the vascular response to tissue damage interact with the coagulation system?
- The coagulation system is also activated in response to tissue damage, and produce thrombin.
- Thrombin induces vascular endothelial cells to secrete Endothelin-1, which produces further vasoconstriction.
Outline the platelet system response to tissue damage.
1) Tissue damage exposes collagen & vFW in the subendothelial matrix
2) Platelet GP1ba binds vFW, leading to platelet tethering at the site of injury
3) Platelet GPVI binds collagen, strengthening adhesion & activating platelets
4) Active platelets develop finger-like projections & secrete: ADP, Thromboxane A2 & 5-HT
5) These factors bind G-protein coupled receptors on already adherent platelets
Binding to GPCRs results in three things:
- Further activation of adherent platelets
- Further vasoconstriction
- And, a conformational change in GP IIb/IIIa, which binds fibrinogen in plasma
What happens is von Willebrand’s disease?
Decreased amount of vFW prevents the proper formation of a platelet plug
What is the function of fibrinogen?
Fibrinogen acts as molecular “glue” between activated GPIIb/IIIa platelets, forming the platelet plug
*Note that the platelet plug is not very strong; the coagulation system is needed to form a secure fibrin clot
What are the factors released by platelets? What is their function?
Platelets release three groups of chemical mediators:
1) Chemokines
2) Dense granules (ADP & 5-HT)
3) Alpha granules, which includes Factor V
Factor V links the platelet system to the coagulation cascade
What is the difference between GPIba, GPVI, GPIIb/IIIa
- GPIba binds vFW to mediate platelet tethering
- GPVI binds collagen for strong platelet adhesion & activation
- GPIIb/IIIa binds fibrinogen, forming the platelet plug
What is the P2Y12 receptor? What drug antagonises this receptor?
Is the receptor for ADP on platelets, which leads to platelet activation
*Plavix is a P2Y12 antagonist
What are PARs? Why are PARs important?
PAR stands for “Protease activated receptors,” which are GPCRs on the surface of platelets that are activated by thrombin
*Activation of PARs leads to further platelet activation & is important because this links the platelet & coagulation systems
What is the Thromboxane A2 receptor?
A platelet receptor
Thromboxane A2 works in an autocrine fashion, increasing platelet activation; it also is a vasoconstrictor
What are Collagen, vWF, and fibrinogen ligands for?
Collagen= GPVI vFW= GPIba Fibrinogen= GPIIb/IIIa
What are Thromboxane A2, ADP, & thrombin ligands for?
TXA2R
P2Y12R (plavix antagonist)
PARs
What mechansisms prevent unnecessary platelet adhesion & activation in nearby uninjured endothelium?
Healthy vasculature has anti-platelet adhesion properties
- Vascular endothelial cells release NO & prostacylin 2, both of which induce vasodilaiton
How does the Blood coagulation system differ from the platelet coagulation system?
Coagulation system forms Fibrin clots, which are much more secure than platelet plugs
How is fibrin made?
- Thrombin is a protease cleaves fibrinogen into fibrin monomers (fibrinogen is synthesized in the liver)
- Fibrin monomers spontaneously form fibrin fibers
- Thrombin also activates Factor XIII, which induces fibrin cross-linking (forming a stable & strong clot)
What are the three general steps of the coagulation cascade? What is the ultimate goal of the coagulation cascade?
1) Formation of the Prothrombin Activator Complex, which converts prothrombin to thrombin
2) Thrombin conversion of fibrinogen to fibrin
3) Factor XIII production to cross-link fibrin
Ultimate goal: Make fibrin & Factor XIII
*Note that prothrombin is continuously synthesized by the liver
What is Factor I called?
Fibrinogen
What is Factor II?
Prothrombin
What is Factor III?
Tissue factor
What is factor IV?
Ca++
Outline the intrinsic pathway. When is the intrinsic pathways activated?
- Initiated when Factor XII binds to exposed collagen at the site of injury & is activated.
- Consequently, Factors XI & IX are activated
- Factor IXa slowly activates Factor X, which cleaves prothrombin to thrombin
- Thrombin feeds back to form Factor VIIIa, which forms the “Tenase Complex” with factor IXa, and by activating Factor V or the Prothrombin Activator Complex–BOTH of these SIGNIFICANTLY accelerate activation thrombin
XII, XI, IX, VIII
Outline the extrinsic pathway. When is the extrinsic pathways activated?
- Sub-endothelial tissue constitutively expresses Tissue Factor (Factor III)
- Tissue damage exposes Factor III to Factor VII, forming Factor VIIa
- Tissue Factor (Factor III), Factor VIIa, & Ca++ form a complex that activates Factor X
Where do the intrinsic & extrinsic pathways converge?
Factor Xa
What is the tenase complex?
Factor VIIIa
Factor IXa
Ca++
Platelet phospholipids
These significantly increase the formation of Factor Xa, which then cleaves prothrombin to thrombin
What deficiency causes Hemophilia A?
Factor VIIIa reduction
Outline the common pathway.
- Factors Xa & Va cleave Prothrombin to Thrombin
- Thrombin cleaves fibrinogen to fibrin
- Thrombin also activates XIIIa, which stabilizes the Fibrin clot
What are the four coagulation factors that require Vitamin K?
X
IX
VII
II
Remember “Vitamin K was born in 1972 (1 is a 10)”
What is the function of Vitamin K?
Reduced vitamin K is a cofactor in the carboxylation of key glutamate residues in coagulation factors, which allows Ca++ to bind & activate the factor
What is the mechanism of action of Warfarin?
Warfarin blocks the reduction of Vitamin K
How is coagulation time measured? What is the difference between an aPTT & PT?
1) aPTT= activated partial thromboplastin time, which measures the speed of the intrinsic pathway
2) PT= Prothrombin time, which is a measure of the extrinsic pathway
What is the function of the anticoagulation system?
Reduction of coagulation system activity to prevent it from running out of control
What are the two mechanisms of the anticoagulation system?
1) Prevention of thrombin-mediated fibrin clot formation, by inhibiting coagulation factors
2) Destruction of formed thrombin
Outline the pathway of the reduction in thrombin production.
- Thrombin can decrease further production of itself by interacting with Thrombomodulin
- Thrombomodulin is an integral membrane protein of endothelial cells
- Thrombomodulin can bind thrombin & protein C (blood plasma protein) to form APC (activated protein C)
- APC interaction with a cofactor, protein S, to form a serine protease that degrades Factors VIIIa & Factor Va
What is Factor V Leiden thrombophilia?
A mutation in Factor V prevents it from being inactivated & leads to a hypercoagulable state
What is the consequence of a deficiency in protein C?
Hypercoaguable state
Outline that mechanism by which activated thrombin is destroyed.
Tissue Factor Pathway Inhibitor (TFPI) is secreted by the vasculature
- TFPI reduces thrombin formation by inhibiting the Factor VIIa/Tissue factor complex
Antithrombin is a circulating plasma protease produced by the liver; it inhibits thrombin production & destroys thrombin already produced
What is the role of Heparin sulfate in anticoagulation?
Heparin sulfate binds to antithrombin & speeds thrombin proteolysis (x1000)
*Note that Heparin has NO DIRECT ANTICOAGULATION effect
How do platelets interact with Heparin?
Activated platelets negatively regulate the anticoagulation system by heparin neutralizing factor
What is the function of the fibrinolytic system?
Degradation of fibrin clots after an injury has healed
Degradation of fibrin clots that form at inappropriate sites
Outline the Fibrinolyitc system.
- Plasmin is created by the cleavage of plasminogen by tPA (Tissue Activating Factor)
- Plasmin is a serine proteases the cleaves fibrin; thus, degrading clots
